Mitochondrial Fission Contributes to Mitochondrial Dysfunction and Insulin Resistance in Skeletal Muscle
Open accessAbstract
Mitochondrial dysfunction in skeletal muscle has been implicated in the development of insulin resistance and type 2 diabetes. Considering the importance of mitochondrial dynamics in mitochondrial and cellular functions, we hypothesized that obesity and excess energy intake shift the balance of mitochondrial dynamics, further contributing to mitochondrial dysfunction and metabolic deterioration in skeletal muscle. First, we revealed that excess palmitate (PA), but not hyperglycemia, hyperinsulinemia, or elevated tumor necrosis factor alpha, induced mitochondrial fragmentation and increased mitochondrion-associated Drp1 and Fis1 in differentiated C2C12 muscle cells. This fragmentation was associated with increased oxidative stress, mitochondrial depolarization, loss of ATP production, and reduced insulin-stimulated glucose uptake. Both genetic and pharmacological inhibition of Drp1 attenuated PA-induced mitochondrial fragmentation, mitochondrial depolarization, and insulin resistance in C2C12 cells. Furthermore, we found smaller and shorter mitochondria and increased mitochondrial fission machinery in the skeletal muscle of mice with genetic obesity and those with diet-induced obesity. Inhibition of mitochondrial fission improved the muscle insulin signaling and systemic insulin sensitivity of obese mice. Our findings indicated that aberrant mitochondrial fission is causally associated with mitochondrial dysfunction and insulin resistance in skeletal muscle. Thus, disruption of mitochondrial dynamics may underlie the pathogenesis of muscle insulin resistance in obesity and type 2 diabetes.
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TL;DR
Excess palmitate, but not hyperglycemia, hyperinsulinemia, or TNF-α, induced mitochondrial fragmentation and insulin resistance in C2C12 muscle cells, and inhibiting mitochondrial fission improved mitochondrial function and insulin sensitivity. Obese mice also showed increased mitochondrial fission machinery in skeletal muscle, and pharmacological fission inhibition improved muscle insulin signaling and systemic insulin sensitivity.
Key findings
- Palmitate (PA) shifted C2C12 mitochondria toward fission in a time- and dose-dependent manner; saturated FAs myristate and PA induced fragmentation, whereas stearate and unsaturated FAs palmitoleate, oleate, and linoleate did not, and oleate, linoleate, or DHA attenuated PA-induced fragmentation.
- PA treatment decreased mitochondrial membrane potential and total ATP content, increased intracellular ROS, and reduced insulin-stimulated glucose uptake; DHA or the ROS scavenger α-tocopherol reversed PA-induced ROS and/or fragmentation, and DHA reversed the membrane-potential and ATP decreases.
- In PA-treated C2C12 cells, mitochondrion-associated Drp1 and Fis1 increased, while Mfn1, Mfn2, and Opa1 did not change; dominant-negative Drp1, Drp1 shRNA, or Mdivi-1 restored PA-induced mitochondrial fragmentation, depolarization, and insulin-stimulated glucose uptake.
- In obese mice, gastrocnemius mitochondria were smaller and shorter; ob/ob mice had increased mitochondrion-associated Drp1 and Fis1, and high-fat-fed mice had increased Fis1 at 10 and 16 weeks and increased Drp1 at 16 weeks. Mdivi-1 (44 mg/kg) increased insulin-stimulated phosphorylation of IRS-1 Tyr608, Akt Ser473, and GSK-3α Ser21, modestly decreased plasma insulin during OGTT, and significantly lowered the insulin resistance index in ob/ob mice, without changing glucose clearance.
Methods
- Differentiated C2C12 skeletal muscle cells were treated with glucose, insulin, TNF-α, or various fatty acids, including PA, and analyzed for mitochondrial morphology, ROS, mitochondrial polarization, ATP content, glucose uptake, mtDNA content, gene expression, and immunoblotting of mitochondrial dynamics proteins.
- Mice included leptin-deficient ob/ob mice and control littermates, plus 8-week-old male C57BL/6 mice fed a high-fat or low-fat diet for 10 or 16 weeks; gastrocnemius muscle mitochondria were assessed by transmission electron microscopy and immunoblotting, and ob/ob mice received Mdivi-1 or vehicle before insulin stimulation or oral glucose tolerance testing.
- Statistical analyses used two-way ANOVA with treatment and experiment as factors, Student’s t test for within-experiment group comparisons, and significance at P < 0.05.
Limitations
- Stated: the cell-culture results involve acute PA treatment, whereas the animal data reflect chronic effects; the authors note uncertainty about whether culture findings are relevant to adult muscle tissue, because obese mice encounter long-term excess FFAs plus other nutrient and inflammatory stimuli and inputs from other organs, while cultured cells encounter relatively short-term excess FFAs alone.
- Stated: short-term lipid infusion in humans or 4-week high-fat feeding in mice may not alter mitochondrial content, morphology, and respiration before demonstrable obesity, leaving open how acute high-fat feeding relates to in vivo mitochondrial morphology.
- Evident from the text: the study is limited to C2C12 cells and rodent models, with no human skeletal muscle data; Mdivi-1 did not change glucose clearance during OGTT and only modestly decreased plasma insulin, and the increase in mitochondrion-associated Drp1 in high-fat-fed mice was not detected at 10 weeks, possibly correlating with degree of body weight increase.
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- Findingown data§ RESULTS
Mdivi-1 ameliorates PA-induced mitochondrial depolarization in C2C12 cells.
“it effectively ameliorated PA-induced ROS generation and mitochondrial depolarization, as well as PA-induced reduction of insulin-stimulated glucose uptake, in a dose-dependent manner (Fig. 6B to D).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Saturated fatty acids myristate (MA) and palmitate (PA) lead to mitochondrial fragmentation in C2C12 cells.
“mitochondrial fragmentation was observed in the groups treated with MA for 6 h and 12 h, which was similar to the effect on the groups treated with PA.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
PA decreases total ATP content in C2C12 cells.
“the total ATP content, reflecting cellular energy production, was decreased in the presence of PA”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Drp1 and Fis1 are significantly increased in the mitochondrial fraction of ob/ob mouse muscle.
“Drp1 and Fis1 were significantly increased in the mitochondrial fraction of ob/ob mouse muscle.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Cotreatment with DHA or alpha-tocopherol (TCP) attenuates PA-induced increase in intracellular ROS levels in C2C12 cells.
“Cotreatment with DHA or α-tocopherol (TCP), a ROS scavenger, significantly attenuated the increased ROS levels induced by PA (Fig. 4A).”
Quote in the paperSubstantial claim
- Findingown data§ RESULTS
TCP cotreatment is associated with recovery of ATP production efficiency after PA in C2C12 cells.
“The amelioration of PA-induced mitochondrial fragmentation by cotreatment with TCP was associated with the recovery of ATP production efficiency (Fig. 4C).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
TNF-alpha (up to 1 pM) for 12 h does not alter mitochondrial tubular morphology in C2C12 cells.
“Similarly, incubation for 12 h at high concentrations of insulin (up to 1.2 μM) and tumor necrosis factor alpha (TNF-α; up to 1 pM) was without effect on the change of mitochondrial tubular feature (data not shown).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
High insulin concentrations (up to 1.2 μM) for 12 h do not alter mitochondrial tubular morphology in C2C12 cells.
“Similarly, incubation for 12 h at high concentrations of insulin (up to 1.2 μM) and tumor necrosis factor alpha (TNF-α; up to 1 pM) was without effect on the change of mitochondrial tubular feature (data not shown).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
DHA cotreatment reverses PA-induced decrease in mitochondrial membrane potential in C2C12 cells.
“Cotreatment with DHA completely reversed the decrease in mitochondrial membrane potential (Fig. 3A).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
DHA cotreatment ameliorates PA-induced expression of Cpt1b, Acsl1, and Acox1 in C2C12 cells.
“While cotreatment with DHA significantly ameliorated the PA-induced expression of Cpt1b, Acsl1, and Acox1, cotreatment with TCP only attenuated the PA-induced expression of Cpt1b (Fig. 4D).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
Fis1 is significantly increased in the mitochondrial fraction of ob/ob mouse muscle.
“Drp1 and Fis1 were significantly increased in the mitochondrial fraction of ob/ob mouse muscle.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
High-fat diet-induced obese mice exhibit smaller and shorter mitochondria in gastrocnemius skeletal muscle than control lean mice.
“Both mice with genetically induced obesity (ob/ob) (Fig. 7A and B) and those with HF diet-induced obesity (data not shown) exhibited smaller and shorter mitochondria in the gastrocnemius skeletal muscle than those from the respective control lean mice.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Genetic inhibition or knockdown of Drp1 restores PA-induced reduction of insulin-stimulated glucose uptake in C2C12 cells.
“inhibition or knockdown of Drp1 restored the PA-induced reduction of insulin-stimulated glucose uptake (Fig. 5E and H).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
High glucose concentrations do not alter mitochondrial tubular morphology in C2C12 cells.
“No difference in the tubular feature of mitochondrial morphology was observed between cells treated with a low glucose concentration (5.6 mM) and those treated with a high glucose concentration (25 mM) for 12 h (Fig. 1A).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
Cotreatment with unsaturated fatty acids OA and LA and polyunsaturated fatty acid DHA, but not saturated fatty acid SA, attenuates PA-induced mitochondrial fragmentation in C2C12 cells.
“Cotreatment with the unsaturated FAs OA and LA and the polyunsaturated FA DHA, but not with the saturated FA SA, attenuated PA-induced mitochondrial fragmentation in C2C12 cells (Fig. 2B).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Mdivi-1 ameliorates PA-induced ROS generation in C2C12 cells.
“it effectively ameliorated PA-induced ROS generation and mitochondrial depolarization, as well as PA-induced reduction of insulin-stimulated glucose uptake, in a dose-dependent manner (Fig. 6B to D).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Genetic inhibition of Drp1 attenuates PA-induced mitochondrial depolarization in C2C12 cells.
“Overexpression of dominant negative Drp1 (DN-Drp1; Drp1-K38A) or Drp1 protein level downregulation by Drp1 shRNA (Fig. 5B) significantly restored PA-induced mitochondrial fragmentation (Fig. 5C and F) and mitochondrial depolarization (Fig. 5D and G).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
ob/ob mice exhibit smaller and shorter mitochondria in gastrocnemius skeletal muscle than control lean mice.
“Both mice with genetically induced obesity (ob/ob) (Fig. 7A and B) and those with HF diet-induced obesity (data not shown) exhibited smaller and shorter mitochondria in the gastrocnemius skeletal muscle than those from the respective control lean mice.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
PA decreases mitochondrial membrane potential in C2C12 cells.
“Treatment with PA for 6 h and 12 h significantly decreased the mitochondrial membrane potential of C2C12 cells.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Excess palmitate (PA) induces mitochondrial fragmentation in differentiated C2C12 muscle cells.
“In contrast, mitochondrial morphology was shifted toward a fragmented, discontinuous network, with a higher proportion of smaller and rounder mitochondria, when cells were treated with one of the most abundant FAs, PA (Fig. 1A).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Pharmacological inhibition of Drp1 by Mdivi-1 partially reverses PA-induced mitochondrial fragmentation in C2C12 cells.
“Although treatment with Mdivi-1 partially reversed PA-induced mitochondrial fragmentation (Fig. 6A)”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
TCP cotreatment only attenuates PA-induced expression of Cpt1b in C2C12 cells.
“While cotreatment with DHA significantly ameliorated the PA-induced expression of Cpt1b, Acsl1, and Acox1, cotreatment with TCP only attenuated the PA-induced expression of Cpt1b (Fig. 4D).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
DHA cotreatment reverses PA-induced decrease in total ATP content in C2C12 cells.
“this phenomenon was reversed by cotreatment with DHA (Fig. 3B).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Levels of Mfn1, Mfn2, and Opa1 are not altered in muscles from high-fat-fed mice.
“Consistently, levels of proteins related to mitochondrial fusion, including Mfn1, Mfn2, and Opa1, were not altered in muscles from HF-fed mice (Fig. 7D).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Genetic inhibition of Drp1 (DN-Drp1 or Drp1 shRNA) attenuates PA-induced mitochondrial fragmentation in C2C12 cells.
“Overexpression of dominant negative Drp1 (DN-Drp1; Drp1-K38A) or Drp1 protein level downregulation by Drp1 shRNA (Fig. 5B) significantly restored PA-induced mitochondrial fragmentation (Fig. 5C and F)”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
PA increases intracellular reactive oxygen species (ROS) levels in C2C12 cells.
“treatment with PA significantly increased intracellular ROS levels, reflected by staining with the fluorescent probe H2DCFDA.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Drp1 level is not altered in mice fed a high-fat diet for 10 weeks.
“While the Drp1 level was not altered in the mice fed an HF diet for 10 weeks, it was significantly increased in the mice fed an HF diet for 16 weeks (Fig. 7E).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
Stearate (SA) and unsaturated fatty acids palmitoleate (PLA), oleate (OA), and linoleate (LA) do not alter mitochondrial tubular morphology in C2C12 cells.
“Treatment of C2C12 cells with SA and all of the unsaturated FAs (PLA, OA, and LA) did not alter the mitochondrial tubular morphology (Fig. 2A).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
PA increases mitochondrion-associated Drp1 and Fis1 in C2C12 cells.
“the levels of mitochondrion-associated proteins Drp1 and Fis1 were greatly increased in the PA-treated group (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
PA treatment does not change levels of mitochondrion-associated Mfn1, Mfn2, and Opa1 in C2C12 cells.
“While no difference in the levels of mitochondrion-associated proteins Mfn1, Mfn2, and Opa1 was detected between PA- and vehicle-treated C2C12 cells”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
TCP cotreatment ameliorates PA-induced mitochondrial fragmentation in C2C12 cells.
“cotreatment with TCP ameliorated PA-induced mitochondrial fragmentation (Fig. 4B).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
PA treatment does not change the ratio of mitochondrial DNA to nuclear DNA in C2C12 cells.
“The ratio of mtDNA to nuclear DNA was not different between the groups treated with and without PA.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Mdivi-1 ameliorates PA-induced reduction of insulin-stimulated glucose uptake in C2C12 cells.
“it effectively ameliorated PA-induced ROS generation and mitochondrial depolarization, as well as PA-induced reduction of insulin-stimulated glucose uptake, in a dose-dependent manner (Fig. 6B to D).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Drp1 is significantly increased in the mitochondrial fraction of ob/ob mouse muscle.
“Drp1 and Fis1 were significantly increased in the mitochondrial fraction of ob/ob mouse muscle.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Drp1 level is significantly increased in mice fed a high-fat diet for 16 weeks.
“While the Drp1 level was not altered in the mice fed an HF diet for 10 weeks, it was significantly increased in the mice fed an HF diet for 16 weeks (Fig. 7E).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Fis1 level is significantly increased in the mitochondrial fraction of muscles from mice fed a high-fat diet for both 10 and 16 weeks.
“The Fis1 level was significantly increased in the mitochondrial fraction of the muscles from mice fed an HF diet for both 10 and 16 weeks.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
PA decreases insulin-stimulated glucose uptake in C2C12 cells.
“While the presence of PA significantly decreased insulin-stimulated glucose uptake in C2C12 cells”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Inhibition of Drp1 by Mdivi-1 in vitro rescued PA-mediated mitochondrial injuries, as indicated by diminished mitochondrial depolarization and ROS generation.
“In our study, inhibition of Drp1 by Mdivi-1 in vitro rescued PA-mediated mitochondrial injuries, as indicated by diminished mitochondrial depolarization and ROS generation.”
Quote in the paperSubstantial claim - Findingreasoning§ DISCUSSION
Drp1 inhibition with Mdivi-1 ameliorated impairment of insulin signal transduction in obese rodent muscle.
“Furthermore, Drp1 inhibition with Mdivi-1 ameliorated the impairment of insulin signal transduction in obese rodent muscle.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Expression of Cpt1b, Lcad, Mcad, and Acsl1 was upregulated in skeletal muscle of ob/ob mice.
“The expression of Cpt1b, Lcad, Mcad, and Acsl1 was upregulated in the skeletal muscle of ob/ob mice, whereas Mdivi-1 treatment showed a tendency to restore the increased gene expression in ob/ob mice (Fig. 9B).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Similar effects of PA on alteration of mitochondrial morphology were found when cells were treated with 200 μM PA for 24 or 48 h.
“In the time course study, we found similar effects of PA on the alteration of mitochondrial morphology when cells were treated with 200 μM PA for 24 or 48 h (data not shown).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Phosphorylation of ERK1/2 and p38 MAPK was increased in skeletal muscle of ob/ob mice compared to control mice.
“The phosphorylation of ERK1/2 and p38 mitogen-activated protein kinase (MAPK) was increased in the skeletal muscle of ob/ob mice, compared to that of control mice (Fig. 9A).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Mdivi-1 treatment did not change glucose clearance after a glucose load in ob/ob mice.
“Although the treatment of Mdivi-1 did not change the clearance of glucose after a glucose load, it modestly decreased plasma insulin levels during the OGTT (Fig. 8B).”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION
Fusion-related proteins Mfn1, Mfn2, and Opa1 were not changed in muscles of mice with ob/ob- or HF-induced obesity or in PA-treated C2C12 cells.
“In agreement with our hypothesis, fusion-related proteins, including Mfn1, Mfn2, and Opa1, were not changed in the muscles of mice with ob/ob- or HF-induced obesity or in PA-treated C2C12 cells.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Treatment of ob/ob mice with 44 mg/kg Mdivi-1 prior to insulin stimulation increased insulin-stimulated phosphorylation at Tyr608 of IRS-1, Ser473 of Akt, and Ser21 of GSK-3α compared to vehicle-treated ob/ob mice.
“Treatment of ob/ob mice with 44 mg/kg Mdivi-1 prior to insulin stimulation increased the insulin-stimulated phosphorylation at Tyr608 of IRS-1, Ser473 of protein kinase B (Akt), and Ser21 of GSK-3α, compared to that in the vehicle-treated group (Fig. 8A).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Mdivi-1 treatment modestly decreased plasma insulin levels during the OGTT in ob/ob mice.
“Although the treatment of Mdivi-1 did not change the clearance of glucose after a glucose load, it modestly decreased plasma insulin levels during the OGTT (Fig. 8B).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
No difference in phosphorylation of JNK was detectable among the three groups.
“No difference in the phosphorylation of JNK was detectable among the three groups.”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION
No evidence of apoptosis, revealed by immunoblotting of cleaved caspase 3, was observed in cells treated with 200 μM PA for 6 h.
“Similarly, no evidence of apoptosis, revealed by immunoblotting of cleaved caspase 3, was observed in cells treated with 200 μM PA for 6 h (data not shown).”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
The insulin resistance index calculated from the OGTT was significantly lower in Mdivi-1-treated ob/ob mice than in vehicle-treated ob/ob mice.
“The insulin resistance index calculated from the OGTT was significantly lower in the Mdivi-1-treated ob/ob mice than in the vehicle-treated ob/ob mice.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Cell toxicity, examined by lactate dehydrogenase assay and crystal violet stain, was exhibited at 48 h of treatment with 200 μM PA.
“Because cell toxicity, examined by lactate dehydrogenase assay and crystal violet stain, was exhibited at 48 h of treatment with 200 μM PA (data not shown), we performed treatment for 6 or 12 h in this study.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Inhibition of Drp1 rendered C2C12 cells resistant to PA-mediated suppression of insulin-stimulated glucose transport.
“Consistently, we found that inhibition of Drp1 rendered C2C12 cells resistant to PA-mediated suppression of insulin-stimulated glucose transport.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
We did not detect an effect of hyperglycemia, hyperinsulinemia, or elevated TNF-α at supraphysiological and pathological concentrations on changes in mitochondrial morphology.
“In the search for extracellular stimuli that induce mitochondrial fission, we did not detect an effect of hyperglycemia, hyperinsulinemia, or elevated TNF-α at supraphysiological and pathological concentrations on changes in mitochondrial morphology.”
Quote in the paperSubstantial claim - Findingown data§ RESULTS
Mdivi-1 treatment showed a tendency to restore the increased gene expression of Cpt1b, Lcad, Mcad, and Acsl1 in ob/ob mice.
“The expression of Cpt1b, Lcad, Mcad, and Acsl1 was upregulated in the skeletal muscle of ob/ob mice, whereas Mdivi-1 treatment showed a tendency to restore the increased gene expression in ob/ob mice (Fig. 9B).”
Quote in the paperNot a substantial claim - Findingown data§ RESULTS
Mdivi-1 treatment attenuated the increased phosphorylation of ERK1/2 and p38 in skeletal muscle of ob/ob mice.
“Mdivi-1 treatment attenuated the increased phosphorylation of ERK1/2 and p38 in the skeletal muscle of ob/ob mice.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
None of the unsaturated or polyunsaturated FAs tested affected mitochondrial fission.
“None of the unsaturated or polyunsaturated FAs we tested affected mitochondrial fission.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Inhibition of mitochondrial fission protected muscle cells against mitochondrial dysfunction and insulin resistance in vitro.
“Inhibition of mitochondrial fission protected muscle cells against mitochondrial dysfunction and insulin resistance in vitro and, more importantly, improved muscle insulin signaling and systemic insulin sensitivity in vivo.”
Quote in the paperSubstantial claim- Rests on an assumption: The ob/ob and high-fat-fed mouse models and PA-treated C2C12 cells are valid models of skeletal muscle insulin resistance in human obesity/type 2 diabetes.
- Findingown data§ DISCUSSION
Saturated FAs MA and PA induced mitochondrial fission.
“For example, while the saturated FAs MA and PA induced mitochondrial fission, SA had no effect despite being only two carbon atoms longer than PA.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
SA had no effect on mitochondrial fission despite being only two carbon atoms longer than PA.
“For example, while the saturated FAs MA and PA induced mitochondrial fission, SA had no effect despite being only two carbon atoms longer than PA.”
Quote in the paperNot a substantial claim - Findingown data§ DISCUSSION
Blocking of mitochondrial fission significantly alleviated PA-induced ROS generation.
“Furthermore, blocking of mitochondrial fission significantly alleviated PA-induced ROS generation (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Genes related to FA oxidation were upregulated in PA-treated cells and ob/ob mouse muscles.
“Our data showed that genes related to FA oxidation were upregulated in PA-treated cells and ob/ob mouse muscles, suggesting that FA oxidation is increased in response to PA or lipid overload.”
Quote in the paperSubstantial claim - Findingown data§ DISCUSSION
Cotreatment with unsaturated and polyunsaturated FAs alleviated PA-induced mitochondrial fission.
“Interestingly, cotreatment with unsaturated and polyunsaturated FAs alleviated PA-induced mitochondrial fission.”
Quote in the paperSubstantial claim - Interpretationown data§ Abstract
Aberrant mitochondrial fission is causally associated with mitochondrial dysfunction and insulin resistance in skeletal muscle.
“Our findings indicated that aberrant mitochondrial fission is causally associated with mitochondrial dysfunction and insulin resistance in skeletal muscle.”
Quote in the paperSubstantial claim - Premisecitation§ INTRODUCTION
Mitochondrial dysfunction and impairment of oxidative capacity in skeletal muscle are key mechanisms mediating insulin resistance.
“Substantial evidence shows that mitochondrial dysfunction and impairment of the oxidative capacity in skeletal muscle are key mechanisms mediating insulin resistance (24, 34).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationreasoning§ Abstract
Disruption of mitochondrial dynamics may underlie the pathogenesis of muscle insulin resistance in obesity and type 2 diabetes.
“Thus, disruption of mitochondrial dynamics may underlie the pathogenesis of muscle insulin resistance in obesity and type 2 diabetes.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION
Mdivi-1 attenuates mitochondrial fragmentation by selectively inhibiting the assembly and GTPase activity of Drp1.
“Mdivi-1 attenuates mitochondrial fragmentation by selectively inhibiting the assembly and GTPase activity of Drp1 (7).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Cassidy-Stone A, 2008, Dev. Cell source
Not checked in the free run.
- Interpretationown data§ DISCUSSION
The fission machinery is likely the main component involved in regulation of mitochondrial dynamics in the in vivo and in vitro models.
“Instead, the fission machinery is likely the main component involved in the regulation of mitochondrial dynamics in our in vivo and in vitro models.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
Consistent increases of mitochondrion-associated Fis1 both in vivo and in vitro support the idea that mitochondria are equipped with fission machinery under this circumstance.
“Nevertheless, the consistent increases of mitochondrion-associated Fis1 both in vivo and in vitro support the idea that mitochondria are equipped with fission machinery under this circumstance.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
Fis1, at least in part, is the cause of increased mitochondrial fission in the muscle of obese mice and PA-treated cultured muscle cells.
“These findings further suggest that Fis1, at least in part, is the cause of increased mitochondrial fission in the muscle of obese mice and PA-treated cultured muscle cells.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
Exposure of muscle cells to PA is deleterious to mitochondrial architecture.
“Nevertheless, our results at least suggest that the exposure of muscle cells to PA is deleterious to mitochondrial architecture.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
Our results provide a rationale for development of muscle insulin resistance in response to lipid flux.
“Thus, our results provide a rationale for the development of muscle insulin resistance in response to lipid flux.”
Quote in the paperSubstantial claim - Interpretationcitation§ DISCUSSION
Sustained hyperglycemia is the cause of mitochondrial fission.
“These studies all support the notion that sustained hyperglycemia is the cause of mitochondrial fission.”
Quote in the paperNot a substantial claim - Premisecitation§ DISCUSSION
Short-term lipid infusion for 6 to 8 h in healthy individuals does not change mitochondrial content, morphology, and respiration rates in skeletal muscle despite a lower mitochondrial membrane potential.
“Short-term lipid infusion for 6 to 8 h in healthy individuals does not change mitochondrial content, morphology, and respiration rates in skeletal muscle despite a lower mitochondrial membrane potential (4, 10).”
Quote in the paperNot a substantial claim0 of 2 sources checked - Interpretationreasoning§ DISCUSSION
These metabolites are associated with insulin resistance by impairing the insulin-signaling pathways.
“These metabolites are associated with insulin resistance by impairing the insulin-signaling pathways.”
Quote in the paperSubstantial claim - Premisecitation§ INTRODUCTION
High-fat diets downregulate genes related to mitochondrial biogenesis and the electron transport chain in muscle tissues from mice and humans.
“High-fat diets downregulate the genes related to mitochondrial biogenesis and the electron transport chain in muscle tissues from mice and humans (3, 40), suggesting that excess dietary fat impairs mitochondrial biogenesis and function.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [3] Bonnard C, 2008, J. Clin. Invest.
Not checked in the free run.
- cites [40] Sparks LM, 2005, Diabetes source
Not checked in the free run.
- Premisecitation§ RESULTS
Mdivi-1 attenuates mitochondrial fission by selectively blocking GTPase activity of Drp1.
“Mdivi-1 is a chemical compound which attenuates mitochondrial fission by selectively blocking GTPase activity of Drp1 (7)”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [7] Cassidy-Stone A, 2008, Dev. Cell source
Not checked in the free run.
- Interpretationreasoning§ DISCUSSION
The fact that mitochondrion-associated Drp1 was increased in ob/ob mouse muscle might explain the efficacy of direct inhibition of Drp1 GTPase activity with Mdivi-1 in attenuation of metabolic deterioration in vivo.
“The fact that mitochondrion-associated Drp1 was increased in ob/ob mouse muscle might explain the efficacy of the direct inhibition of Drp1 GTPase activity with Mdivi-1 in the attenuation of metabolic deterioration in vivo.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION
Elevated circulating lipid and inflammatory cytokines usually occur prior to development of hyperinsulinemia and hyperglycemia during progression of type 2 diabetes.
“Although many studies demonstrated the effect of hyperglycemia on increased generation of ROS and mitochondrial fission in a variety of cell types (26, 48), elevated circulating lipid and inflammatory cytokines usually occur prior to the development of hyperinsulinemia and hyperglycemia during the progression of type 2 diabetes (27, 38).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data§ DISCUSSION
The fusion machinery is not much affected in skeletal muscle of obese rodents or in PA-treated C2C12 cells.
“Our results suggest that the fusion machinery is not much affected in the skeletal muscle of obese rodents or in PA-treated C2C12 cells.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
PA does not largely affect signaling and cellular processes that could be linked to cellular death under the experimental conditions and time course studied.
“Thus, our data suggest that PA does not largely affect signaling and cellular processes that could be linked to cellular death under the experimental conditions and time course we studied.”
Quote in the paperSubstantial claim - Premisecitation§ DISCUSSION
Obesity induced by HF diet leads to enhanced oxidative stress in rodents.
“Thus, obesity induced by an HF diet leads to enhanced oxidative stress in rodents (3, 46).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [3] Bonnard C, 2008, J. Clin. Invest.
Not checked in the free run.
- cites [46] Wellen KE, 2010, Mol. Cell source
Not checked in the free run.
- Interpretationown data§ DISCUSSION
Increased ROS levels in response to excess PA are the direct cause of mitochondrial fragmentation.
“Our study demonstrated that increased ROS levels in response to excess PA are the direct cause of mitochondrial fragmentation, because decreasing ROS levels with a scavenger prevented PA-induced mitochondrial fission (Fig. 4B).”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
Diverse effects of different FAs on mitochondrial morphology correlated with their impacts on mitochondrial and cellular functions.
“Thus, the diverse effects of different FAs on mitochondrial morphology correlated with their impacts on mitochondrial and cellular functions.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
FA oxidation is increased in response to PA or lipid overload.
“Our data showed that genes related to FA oxidation were upregulated in PA-treated cells and ob/ob mouse muscles, suggesting that FA oxidation is increased in response to PA or lipid overload.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
Disruption of mitochondrial dynamics in skeletal muscle may underlie pathogenesis of insulin resistance.
“Thus, our results establish a causative link between mitochondrial dynamics and metabolic deterioration and imply that disruption of mitochondrial dynamics in skeletal muscle may underlie the pathogenesis of insulin resistance.”
Quote in the paperSubstantial claim- Rests on an assumption: The ob/ob and high-fat-fed mouse models and PA-treated C2C12 cells are valid models of skeletal muscle insulin resistance in human obesity/type 2 diabetes.
- Rests on an assumption: Changes in phosphorylation of IRS-1, Akt, GSK-3α, ERK1/2, and p38 reflect insulin signaling and insulin sensitivity.
- Rests on an assumption: The insulin resistance index calculated from the OGTT is a valid measure of systemic insulin sensitivity.
- Premisecitation§ DISCUSSION
ROS can function as signaling molecules to activate MAPK family, including ERK, p38, and JNK.
“ROS can function as signaling molecules to activate the MAPK family, including ERK, p38, and JNK (15, 25).”
Quote in the paperSubstantial claim0 of 2 sources checked - Premisecitation§ DISCUSSION
Increased FA oxidation in muscle tissue was found in several HF-fed rodent models.
“While reduced FA oxidation was observed in obese human muscle (39, 42), increased FA oxidation in muscle tissue was found in several HF-fed rodent models (19, 43).”
Quote in the paperSubstantial claim0 of 2 sources checked - Interpretationown data§ DISCUSSION
Our results establish a causative link between mitochondrial dynamics and metabolic deterioration.
“Thus, our results establish a causative link between mitochondrial dynamics and metabolic deterioration and imply that disruption of mitochondrial dynamics in skeletal muscle may underlie the pathogenesis of insulin resistance.”
Quote in the paperSubstantial claim- Rests on an assumption: The ob/ob and high-fat-fed mouse models and PA-treated C2C12 cells are valid models of skeletal muscle insulin resistance in human obesity/type 2 diabetes.
- Rests on an assumption: Changes in phosphorylation of IRS-1, Akt, GSK-3α, ERK1/2, and p38 reflect insulin signaling and insulin sensitivity.
- Rests on an assumption: The insulin resistance index calculated from the OGTT is a valid measure of systemic insulin sensitivity.
- Interpretationown data§ DISCUSSION
ROS resulted from nutrient excess or PA exposure is deleterious to mitochondrial architecture and dynamics in muscle tissue/cells.
“Thus, our study indicated that ROS resulted from nutrient excess or PA exposure is deleterious to mitochondrial architecture and dynamics in muscle tissue/cells.”
Quote in the paperSubstantial claim - Interpretationreasoning§ DISCUSSION
These results support link between mitochondrial morphology, ROS generation, and activation of MAPK family in regulation of insulin signaling pathway.
“These results support the link between mitochondrial morphology, ROS generation, and activation of the MAPK family in the regulation of the insulin signaling pathway.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
There is a tight association and interplay between ROS generation and mitochondrial fission.
“These data imply a tight association and interplay between ROS generation and mitochondrial fission.”
Quote in the paperSubstantial claim - Interpretationown data§ DISCUSSION
Attenuation of increased FA oxidation occurs in presence of DHA or Mdivi-1.
“Interestingly, cotreatment of PA-treated cells with DHA or inhibition of fission by Mdivi-1 in ob/ob mice reversed upregulated genes, suggesting the attenuation of increased FA oxidation in the presence of DHA or Mdivi-1.”
Quote in the paperSubstantial claim
- May combine two claims. 24
- Classified as probably not a substantial claim. 26
May combine two claims.
Findingown data§ AbstractInhibition of mitochondrial fission improves muscle insulin signaling and systemic insulin sensitivity of obese mice.
“Inhibition of mitochondrial fission improved the muscle insulin signaling and systemic insulin sensitivity of obese mice.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ RESULTSPA treatment increases expression of Cpt1b, Lcad, Acsl1, and Acox1, but not Mcad, in C2C12 cells.
“Except for medium-chain acyl coenzyme A (acyl-CoA) dehydrogenase (Mcad), the expression of carnitine palmitoyltransferase 1b (Cpt1b), long-chain acyl-CoA dehydrogenase (Lcad), long-chain fatty acid CoA ligase 1 (Acsl1), and acyl-CoA oxidase 1 (Acox1) was significantly increased by PA treatment.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown data§ DISCUSSIONFission-related protein Drp1 was increased in PA-treated C2C12 cells and in muscles from ob/ob mice and mice fed an HF diet for 16 weeks but not altered in muscles from mice fed an HF diet for 10 weeks.
“Another fission-related protein, Drp1, was increased in PA-treated C2C12 cells and in muscles from ob/ob mice and mice fed an HF diet for 16 weeks but not altered in muscles from mice fed an HF diet for 10 weeks.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ DISCUSSIONFission-related protein Fis1 was significantly increased both in muscles from obese rodents and in PA-treated C2C12 cells.
“In contrast, the fission-related protein Fis1 was significantly increased both in muscles from obese rodents and in PA-treated C2C12 cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ DISCUSSIONCotreatment of PA-treated cells with DHA or inhibition of fission by Mdivi-1 in ob/ob mice reversed upregulated genes.
“Interestingly, cotreatment of PA-treated cells with DHA or inhibition of fission by Mdivi-1 in ob/ob mice reversed upregulated genes, suggesting the attenuation of increased FA oxidation in the presence of DHA or Mdivi-1.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data§ DISCUSSIONMitochondrial fission occurs in skeletal muscle of obese animals and in cultured muscle cells in response to high levels of some saturated FAs.
“In conclusion, we provide evidence that mitochondrial fission occurs in the skeletal muscle of obese animals and in cultured muscle cells in response to high levels of some saturated FAs.”
Quote in the paperSubstantial claim- Rests on an assumption: The ob/ob and high-fat-fed mouse models and PA-treated C2C12 cells are valid models of skeletal muscle insulin resistance in human obesity/type 2 diabetes.
May combine two claims.
Findingown data§ DISCUSSIONInhibition of mitochondrial fission improved muscle insulin signaling and systemic insulin sensitivity in vivo.
“Inhibition of mitochondrial fission protected muscle cells against mitochondrial dysfunction and insulin resistance in vitro and, more importantly, improved muscle insulin signaling and systemic insulin sensitivity in vivo.”
Quote in the paperSubstantial claim- Rests on an assumption: The ob/ob and high-fat-fed mouse models and PA-treated C2C12 cells are valid models of skeletal muscle insulin resistance in human obesity/type 2 diabetes.
- Rests on an assumption: Changes in phosphorylation of IRS-1, Akt, GSK-3α, ERK1/2, and p38 reflect insulin signaling and insulin sensitivity.
- Rests on an assumption: The insulin resistance index calculated from the OGTT is a valid measure of systemic insulin sensitivity.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ INTRODUCTIONIncreased fatty acid uptake contributes to increased lipid accumulation in skeletal muscle, leading to lipotoxicity, which impairs muscle insulin sensitivity.
“Increased fatty acid (FA) uptake contributes to increased lipid accumulation in skeletal muscle, leading to lipotoxicity, which is known to impair muscle insulin sensitivity (2, 20).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductnone given§ MATERIALS AND METHODSNo effect of fatty acids on cell viability under this experimental condition was identified.
“No effect of FAs on cell viability under this experimental condition was identified.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONAn imbalance of mitochondrial networks in neurons favoring mitochondrial fission plays a critical role in the pathogenesis of diabetic neuropathy both in vivo and in vitro.
“For example, two studies demonstrated that an imbalance of mitochondrial networks in neurons favoring mitochondrial fission plays a critical role in the pathogenesis of diabetic neuropathy both in vivo and in vitro (14, 45).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONMany studies demonstrated effect of hyperglycemia on increased generation of ROS and mitochondrial fission in a variety of cell types.
“Although many studies demonstrated the effect of hyperglycemia on increased generation of ROS and mitochondrial fission in a variety of cell types (26, 48), elevated circulating lipid and inflammatory cytokines usually occur prior to the development of hyperinsulinemia and hyperglycemia during the progression of type 2 diabetes (27, 38).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation§ DISCUSSIONThe fine balance between mitochondrial fusion and fission can be upset by a variety of stress responses, including nutrient stress and simulated ischemia.
“Thus, the fine balance between mitochondrial fusion and fission can be upset by a variety of stress responses, including nutrient stress and simulated ischemia.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationcitation§ DISCUSSIONAcute HF feeding might not have the same effect on mitochondrial morphology and dysfunction prior to demonstrable obesity.
“These findings suggest that acute HF feeding might not have the same effect on mitochondrial morphology and dysfunction prior to demonstrable obesity.”
Quote in the paperNot a substantial claimMay combine two claims.
Premisereasoning§ INTRODUCTIONBalanced mitochondrial dynamics is critical to maintenance of functional mitochondria, energy generation, and prevention of apoptosis.
“Nevertheless, balanced mitochondrial dynamics is critical to maintenance of functional mitochondria, energy generation, and prevention of apoptosis.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Interpretationown data§ DISCUSSIONIt is possible that the increase in mitochondrion-associated Drp1 level is correlated with the degree of body weight increase.
“Thus, it is possible that the increase in the mitochondrion-associated Drp1 level is correlated with the degree of body weight increase.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ INTRODUCTIONLack of fission by downregulation of Drp1 expression leads to loss of mitochondrial DNA and a decrease in mitochondrial respiration in HeLa cells.
“Lack of fission by downregulation of Drp1 expression leads to loss of mitochondrial DNA (mtDNA) and a decrease in mitochondrial respiration in HeLa cells (33).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Parone PA, 2008, PLoS One source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONMitochondrial fragmentation is present in coronary endothelial cells from diabetic mice.
“Another study revealed mitochondrial fragmentation in coronary endothelial cells from diabetic mice (26).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [26] Makino A, 2010, Diabetologia source
Not checked in the free run.
Classified as probably not a substantial claim.
Premisecitation§ INTRODUCTIONThe frequencies of fusion and fission events are balanced to maintain the overall morphology of the mitochondrial population.
“The frequencies of fusion and fission events are balanced to maintain the overall morphology of the mitochondrial population (8, 41).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
Interpretationown data§ RESULTSInhibition of mitochondrial fission machinery by a pharmacological inhibitor improved insulin signaling in skeletal muscle and systemic insulin sensitivity in ob/ob mice.
“Thus, the inhibition of mitochondrial fission machinery by a pharmacological inhibitor improved insulin signaling in the skeletal muscle and systemic insulin sensitivity in ob/ob mice.”
Quote in the paperSubstantial claim- Rests on an assumption: Changes in phosphorylation of IRS-1, Akt, GSK-3α, ERK1/2, and p38 reflect insulin signaling and insulin sensitivity.
- Rests on an assumption: The insulin resistance index calculated from the OGTT is a valid measure of systemic insulin sensitivity.
May combine two claims.
Premisecitation§ DISCUSSIONLipid overload impairs oxidative capacity and increases intracellular accumulation of FA-derived metabolites, such as long-chain acyl-CoA, diacylglycerol, ceramide, and triacylglycerol, in skeletal muscle.
“Lipid overload impairs oxidative capacity and increases the intracellular accumulation of FA-derived metabolites, such as long-chain acyl-CoA, diacylglycerol, ceramide, and triacylglycerol, in skeletal muscle (1, 30, 35, 37).”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [1] Abdul-Ghani MA, 2008, Am. J. Physiol. Endocrinol. Metab. source
Not checked in the free run.
- cites [30] Montell E, 2001, Am. J. Physiol. Endocrinol. Metab. source
Not checked in the free run.
- cites [35] Powell DJ, 2004, Biochem. J. source
Not checked in the free run.
- cites [37] Sabin MA, 2007, J. Cell. Physiol. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONExposure to high levels of glucose and PA induced pancreatic β-cell mitochondrial fragmentation.
“Finally, exposure to high levels of glucose and PA induced pancreatic β-cell mitochondrial fragmentation, and preserving mitochondrial dynamics protected β cells from apoptosis (28, 29).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONMitochondrial fission occurs in kidneys and heart after acute ischemia/reperfusion injury in mice.
“For example, mitochondrial fission occurs in the kidneys and heart after acute ischemia/reperfusion injury in mice, and prevention of this process is beneficial (5, 32).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONPreserving mitochondrial dynamics protected β cells from apoptosis.
“Finally, exposure to high levels of glucose and PA induced pancreatic β-cell mitochondrial fragmentation, and preserving mitochondrial dynamics protected β cells from apoptosis (28, 29).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ INTRODUCTIONInhibition of Drp1 prevents the decrease in mitochondrial membrane potential and release of cytochrome c in COS-7 cells.
“another study demonstrated that inhibition of Drp1 prevents the decrease in mitochondrial membrane potential and release of cytochrome c in COS-7 cells (16).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Frank S, 2001, Dev. Cell source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DISCUSSIONHF feeding of mice for 4 weeks does not alter their mitochondrial content and respiration rates.
“Similarly, HF feeding of mice for 4 weeks does not alter their mitochondrial content and respiration rates (3).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] Bonnard C, 2008, J. Clin. Invest.
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONSeveral types of cultured cells from the cardiovascular system exhibited mitochondrial fission under hyperglycemic conditions.
“Several types of cultured cells from the cardiovascular system exhibited mitochondrial fission under hyperglycemic conditions (48).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [48] Yu T, 2008, Cardiovasc. Res. source
Not checked in the free run.
May combine two claims.
Premisecitation§ DISCUSSIONIn humans, average concentration of FFAs in postabsorptive state is 500 to 1,000 μM in plasma, and that of PA can reach 200 μM.
“In humans, the average concentration of FFAs in the postabsorptive state is 500 to 1,000 μM in the plasma, and that of PA can reach 200 μM (17).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [17] Fraser DA, 1999, Rheumatology (Oxford) source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Study design and conductown data§ MATERIALS AND METHODSQuantification of mitochondrial tubular morphology was performed by two investigators blinded to the treatment.
“over three independent experiments by two investigators blinded to the treatment.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONPrevention of mitochondrial fission is beneficial in kidneys and heart after acute ischemia/reperfusion injury in mice.
“For example, mitochondrial fission occurs in the kidneys and heart after acute ischemia/reperfusion injury in mice, and prevention of this process is beneficial (5, 32).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Study design and conductnone given§ DISCUSSIONResults from muscle cells are in acute treatments whereas data from animals are due to chronic effects.
“In our study, we noticed that the results from muscle cells are in acute treatments whereas data from animals are due to chronic effects.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ INTRODUCTIONIntracellular lipid metabolites activate serine/threonine protein kinases and suppress insulin actions.
“the intracellular lipid metabolites have been shown to activate serine/threonine protein kinases and suppress insulin actions (37).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [37] Sabin MA, 2007, J. Cell. Physiol. source
Not checked in the free run.
Classified as probably not a substantial claim. May combine two claims.
Premisecitation§ DISCUSSIONMdivi-1 affects neither the GTPase activity of dynamin 1 nor that of yeast homologs of Mfn1/2 and Opa1.
“It affects neither the GTPase activity of dynamin 1 nor that of yeast homologs of Mfn1/2 and Opa1.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ INTRODUCTIONFibroblasts lacking Mfn1 and Mfn2 completely lack mitochondrial fusion and show severe cellular defects, including poor growth, heterogeneity of mitochondrial membrane potential, and decreased respiration.
“fibroblasts lacking Mfn1 and Mfn2 completely lack mitochondrial fusion and show severe cellular defects, including poor growth, heterogeneity of mitochondrial membrane potential, and decreased respiration (11).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [11] Chen H, 2005, J. Biol. Chem. source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONUnsaturated and ω-3 polyunsaturated FFAs do not alter mitochondrial membrane potential and ATP generation in C2C12 cells.
“For example, saturated FAs reduce mitochondrial membrane potential, as well as ATP generation, in C2C12 cells, while unsaturated and ω-3 polyunsaturated FFAs do not alter these functions (21).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Hirabara SM, 2010, J. Cell. Physiol. source
Not checked in the free run.
May combine two claims.
Interpretationreasoning§ DISCUSSIONImbalance in mitochondrial dynamics would accelerate ROS accumulation, which may further activate signaling molecules, including MAPK family, and suppress insulin signaling.
“Imbalance in the mitochondrial dynamics would accelerate ROS accumulation, which may further activate signaling molecules, including the MAPK family, and suppress insulin signaling.”
Quote in the paperSubstantial claimMay combine two claims.
Premisecitation§ DISCUSSIONActivation of these protein kinases phosphorylates IRS-1 at serine residue(s), which further interrupts tyrosine phosphorylation on IRS-1 and suppresses downstream insulin signaling.
“Other studies demonstrated that activation of these protein kinases phosphorylates IRS-1 at its serine residue(s), which further interrupts tyrosine phosphorylation on IRS-1 and suppresses downstream insulin signaling (12).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [12] De Fea K, 1997, J. Biol. Chem. source
Not checked in the free run.
Probably not a substantial claim: may not pass S2 (checkable).
Interpretationreasoning§ DISCUSSIONManipulation of mitochondrial morphology may provide a novel therapeutic strategy for insulin resistance and type 2 diabetes.
“Finally, manipulation of mitochondrial morphology may provide a novel therapeutic strategy for insulin resistance and type 2 diabetes.”
Quote in the paperNot a substantial claim- Rests on an assumption: The ob/ob and high-fat-fed mouse models and PA-treated C2C12 cells are valid models of skeletal muscle insulin resistance in human obesity/type 2 diabetes.
- Rests on an assumption: Changes in phosphorylation of IRS-1, Akt, GSK-3α, ERK1/2, and p38 reflect insulin signaling and insulin sensitivity.
- Rests on an assumption: The insulin resistance index calculated from the OGTT is a valid measure of systemic insulin sensitivity.
May combine two claims.
Interpretationreasoning§ DISCUSSIONExcessive FA oxidation due to lipid overload leads to formation of free radicals and ROS that can compromise mitochondrial function.
“Thus, it is likely that excessive FA oxidation due to lipid overload leads to the formation of free radicals and ROS that can compromise mitochondrial function.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DISCUSSIONSupplementation of eicosapentaenoate and DHA protects mice from HF-induced body weight gain, dyslipidemia, and glucose intolerance.
“For example, supplementation of eicosapentaenoate and DHA protects mice from HF-induced body weight gain, dyslipidemia, and glucose intolerance (23).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [23] Kuda O, 2009, Diabetologia source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
Premisecitation§ DISCUSSIONDietary supplementation with monounsaturated FAs improves insulin sensitivity and adipokine and lipid profiles in HF-fed mice and healthy young subjects.
“Dietary supplementation with monounsaturated FAs improves insulin sensitivity and adipokine and lipid profiles in the HF-fed mice and healthy young subjects (44, 47).”
Quote in the paperNot a substantial claim0 of 2 sources checkedProbably not a substantial claim: may not pass S3 (load-bearing).
Premisecitation§ DISCUSSIONReduced FA oxidation was observed in obese human muscle.
“While reduced FA oxidation was observed in obese human muscle (39, 42), increased FA oxidation in muscle tissue was found in several HF-fed rodent models (19, 43).”
Quote in the paperNot a substantial claim0 of 2 sources checkedMay combine two claims.
Premisecitation§ DISCUSSIONSaturated FAs reduce mitochondrial membrane potential, as well as ATP generation, in C2C12 cells.
“For example, saturated FAs reduce mitochondrial membrane potential, as well as ATP generation, in C2C12 cells, while unsaturated and ω-3 polyunsaturated FFAs do not alter these functions (21).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [21] Hirabara SM, 2010, J. Cell. Physiol. source
Not checked in the free run.
The paper relies on this without support.
The involvement of mitochondrial dynamics in the pathogenesis of metabolic disorders remains unclear.
“Although decreased mitochondrial function and activity in skeletal muscle has been documented in obesity and type 2 diabetes, the involvement of mitochondrial dynamics in the pathogenesis of metabolic disorders remains unclear.”
The paper relies on this without support.
A high fusion-to-fission ratio leads to elongated, tubular, interconnected mitochondrial networks, whereas a low ratio results in fragmented, discontinuous mitochondria.
“A high fusion-to-fission ratio leads to elongated, tubular, interconnected mitochondrial networks, whereas a low ratio results in fragmented, discontinuous mitochondria.”
The paper relies on this without support.
Mitochondrial fusion and fission are finely regulated by Mfn1, Mfn2, Opa1, Drp1, and Fis1.
“These two opposing processes are finely regulated by the mitochondrial fusion proteins mitofusins 1 and 2 (Mfn1 and Mfn2, respectively) and optic atrophy 1 (Opa1) and by the mitochondrial fission proteins dynamin-related protein 1 (Drp1) and fission protein 1 (Fis1).”
The paper relies on this without support.
The ob/ob and high-fat-fed mouse models and PA-treated C2C12 cells are valid models of skeletal muscle insulin resistance in human obesity/type 2 diabetes.
“We further tested the effects of inhibiting mitochondrial fission on the skeletal muscle of ob/ob mice.”
The paper relies on this without support.
Changes in phosphorylation of IRS-1, Akt, GSK-3α, ERK1/2, and p38 reflect insulin signaling and insulin sensitivity.
“Treatment of ob/ob mice with 44 mg/kg Mdivi-1 prior to insulin stimulation increased the insulin-stimulated phosphorylation at Tyr608 of IRS-1, Ser473 of protein kinase B (Akt), and Ser21 of GSK-3α, compared to that in the vehicle-treated group (Fig. 8A).”
The paper relies on this without support.
The insulin resistance index calculated from the OGTT is a valid measure of systemic insulin sensitivity.
“The insulin resistance index calculated from the OGTT was significantly lower in the Mdivi-1-treated ob/ob mice than in the vehicle-treated ob/ob mice.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Some studies report no alteration of MFN1/2 and OPA1 proteins in palmitic acid-treated C2C12 cells and in obese mice fed a high-fat diet for 10 weeks.
“Interestingly, discrepancies arise in different studies, with some reporting no alteration of MFN1/2 and OPA1 proteins in palmitic acid-treated C2C12 cells and in obese mice fed a high-fat diet for 10 weeks [66].”
From Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds (2024) · cites this paper as [66]
Varying results on mitochondrial dynamics proteins may be attributed to differences in diet duration and body weight changes, suggesting that fusion and fission processes occur at distinct time intervals.
“These varying results may be attributed to differences in diet duration and body weight changes [66], suggesting that fusion and fission processes occur at distinct time intervals.”
From Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds (2024) · cites this paper as [66]
Increasing the fusion-to-fission ratio through genetic and pharmacologic DRP1 inhibition could modify fatty acid-induced mitochondrial fragmentation, depolarization, and insulin resistance in C2C12 cells.
“In this regard, previous study demonstrated that increasing fusion-to-fission ratio through genetic and pharmacologic DRP1 inhibition could modify fatty acid-induced mitochondrial fragmentation, depolarization, and insulin resistance in C2C12 cells [66].”
From Mitochondrial Adaptation in Skeletal Muscle: Impact of Obesity, Caloric Restriction, and Dietary Compounds (2024) · cites this paper as [66]
Aberrant mitochondrial fission is associated with insulin resistance in mouse skeletal muscle.
“Further, alterations in mitochondrial dynamics and in particular in Mfn2, have been associated with a reduced mitochondrial function in skeletal muscle in obesity and T2DM (Zorzano et al., 2009) and recently aberrant mitochondrial fission has been also associated with insulin resistance in mouse skeletal muscle (Jheng et al., 2012).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Jheng et al., 2012
Higher mitochondrial fission has been associated with fat accumulation in genetically induced obesity (ob/ob) mice or in high-fat induced obesity.
“higher mitochondrial fission has been also associated with fat accumulation in genetically induced obesity (ob/ob) mice or in high-fat induced obesity (Jheng et al., 2012)”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Jheng et al., 2012
Aberrant mitochondrial fission has been associated with insulin resistance in mouse skeletal muscle.
“aberrant mitochondrial fission has been also associated with insulin resistance in mouse skeletal muscle (Jheng et al., 2012).”
From Mitochondrial Activity and Dynamics Changes Regarding Metabolism in Ageing and Obesity (2017) · cites this paper as Jheng et al., 2012
Increased mitochondrial fission and consequent mitochondrial fragmentation are associated with increased ROS production, mitochondrial depolarisation, impaired ATP production and decreased insulin-dependent glucose uptake in C2C12 murine cell line.
“Furthermore, increased mitochondrial fission and consequent mitochondrial fragmentation have been associated with increased ROS production, mitochondrial depolarisation, impaired ATP production and decreased insulin-dependent glucose uptake in C2C12 murine cell line (Jheng et al., 2012)”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Jheng et al., 2012
Exposure of C2C12 muscle cells to palmitic acid results in increased mitochondria fission as demonstrated by increased mitochondrial fragmentation orchestrated by upregulation of dynamin-related protein 1 and mitochondrial fission 1 protein.
“In support of this notion, exposure of C2C12 muscle cells to palmitic acid resulted in increased mitochondria fission as demonstrated by increased mitochondrial fragmentation orchestrated by the upregulation of dynamin-related protein 1 and mitochondrial fission 1 protein (Jheng et al., 2012).”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Jheng et al., 2012
Ceramide may represent the downstream effector of the detrimental effect of long-chain saturated fatty acid on mitochondrial health.
“indicating that this lipotoxic metabolite may represent the downstream effector of the detrimental effect of long-chain saturated fatty acid on mitochondrial health.”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Jheng et al., 2012
The palmitic acid-induced increase in mitochondrial fission is associated with increased oxidative stress and loss of ATP synthesis.
“Not surprisingly, this process was associated with increased oxidative stress and loss of ATP synthesis (Jheng et al., 2012)”
From Mitochondrial (Dys)function and Insulin Resistance: From Pathophysiological Molecular Mechanisms to the Impact of Diet (2019) · cites this paper as Jheng et al., 2012
In skeletal muscle, reduced mitochondrial respiration has been linked to aberrant control of mitochondrial dynamics.
“In skeletal muscle, reduced mitochondrial respiration has also been linked to aberrant control of mitochondrial dynamics [64–67].”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [66]
Increased exposure of myotubes to PA and fatty acid derivatives such as ceramide promotes a low mitochondrial fusion to fission ratio, resulting in fragmented, discontinuous mitochondria that exhibit diminished capacity for respiration and ATP synthesis and are thought to be causally linked to impaired insulin sensitivity and metabolic function.
“Increased exposure of myotubes to PA and fatty acid derivatives such as ceramide promote a low mitochondrial fusion to fission ratio resulting in fragmented, discontinuous mitochondria that not only exhibit diminished capacity for respiration and ATP synthesis, but also is thought to be causally linked to impaired insulin sensitivity and metabolic function [66–68].”
From Proinflammatory NFkB signalling promotes mitochondrial dysfunction in skeletal muscle in response to cellular fuel overloading (2019) · cites this paper as [66]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Glucose administration described as both oral and injected
MinorThe glucose tolerance test method says glucose was given orally, but describes blood collection relative to injections rather than the oral bolus.
“Mice were fasted for 4 h and given an oral glucose bolus (2 g/kg body weight).”
“Blood samples were collected before and at indicated times after injections.”
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Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes.
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Impaired Mitochondrial Activity in the Insulin-Resistant Offspring of Patients with Type 2 Diabetes
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Mitochondrial dysfunction and type 2 diabetes
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The Role of Dynamin-Related Protein 1, a Mediator of Mitochondrial Fission, in Apoptosis
Frank, S., Gaume, B., Bergmann-Leitner, E. S., Leitner, W. W., Robert, E. G., Catez, F., Smith, C. L., & Youle, R. J. (2001) · Developmental Cell · doi:10.1016/s1534-5807(01)00055-7 · Cited by 1,755 · see citing works
Evans, J. L., Goldfine, I. D., Maddux, B. A., & Grodsky, G. M. (2003) · Diabetes · doi:10.2337/diabetes.52.1.1 · Cited by 1,482 · see citing works
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“On the other hand, higher mitochondrial fission has been also associated with fat accumulation in genetically induced obesity (ob/ob) mice or in high-fat induced obesity (Jheng et al., 2012) and with insulin resistance in the same mice model (Holmstrom et al., 2012).”
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BackgroundMethodCan Metformin Exert as an Active Drug on Endothelial Dysfunction in Diabetic Subjects
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- Authors
- Jheng, H.-F., Tsai, P.-J., Guo, S.-M., Kuo, L.-H., Chang, C.-S., Su, I.-J., Chang, C.-R., & Tsai, Y.-S.
- Affiliations
- National Cheng Kung University (TW)
- National Tsing Hua University (TW)
- National Health Research Institutes (TW)
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2012-01-01
- Volume
- 32
- Issue
- 2
- Pages
- 309-319
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC3255771
- OpenAlex
- W2063102700
- Semantic Scholar
- 4318951dc3453970d52735b16951b99f27ec8636
- Cited by
- 650
- References
- 48
- Citations by year
- 2026: 26 · 2025: 48 · 2024: 55 · 2023: 64 · 2022: 56 · 2021: 56 · 2020: 64 · 2019: 50 · 2018: 63 · 2017: 54 · 2016: 36 · 2015: 25 · 2014: 23 · 2013: 22 · 2012: 8
- FWCI
- 6.88
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Science Council
- National Health Research Institutes
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- mitochondrial fission, mitochondrial fragmentation, mitochondrial dynamics, insulin resistance, skeletal muscle, type 2 diabetes, obesity, palmitate, Drp1, Fis1, oxidative stress, mitochondrial depolarization, insulin signaling, diet-induced obesity
- MeSH terms
- Animals, Cell Line, Fatty Acids, Glucose, Insulin Resistance, Mitochondria, Muscle, Obesity, Protein Kinases, Reactive Oxygen Species, Muscle, Skeletal, Palmitic Acid, Mitochondrial Proteins, Dynamins, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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