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Cited by 91Mitochondrial Function and PathologyMuscle Physiology and DisordersAutophagy in Disease and Therapy

Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles

Open access
Romanello, Vanina, Scalabrin, Marco, Albiero, Mattia, Blaauw, Bert, Scorrano, Luca, Sandri, Marco·2019·Cells
DOI 10.3390/cells8060597PMC PMC6627087
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Abstract

The maintenance of muscle mass and its ability to function relies on a bioenergetic efficient mitochondrial network. This network is highly impacted by fusion and fission events. We have recently shown that the acute deletion of the fusion protein Opa1 induces muscle atrophy, systemic inflammatory response, precocious epithelial senescence, and premature death that are caused by muscle-dependent secretion of FGF21. However, both fusion and fission machinery are suppressed in aging sarcopenia, cancer cachexia, and chemotherapy-induced muscle wasting. We generated inducible muscle-specific Opa1 and Drp1 double-knockout mice to address the physiological relevance of the concomitant impairment of fusion and fission machinery in skeletal muscle. Here we show that acute ablation of Opa1 and Drp1 in adult muscle causes the accumulation of abnormal and dysfunctional mitochondria, as well as the inhibition of autophagy and mitophagy pathways. This ultimately results in ER stress, muscle loss, and the reduction of force generation. However, the simultaneous inhibition of the fission protein Drp1 when Opa1 is absent alleviates FGF21 induction, oxidative stress, denervation, and inflammation rescuing the lethal phenotype of Opa1 knockout mice, despite the presence of any muscle weakness. Thus, the simultaneous inhibition of fusion and fission processes mitigates the detrimental effects of unbalanced mitochondrial fusion and prevents the secretion of pro-senescence factors.

AI snapshot

Written from the paper’s full text.

TL;DR

Muscle-specific simultaneous deletion of Opa1 and Drp1 in adult mice causes abnormal mitochondria, impaired autophagy/mitophagy, ER stress, muscle atrophy, and weakness, but also mitigates the lethal systemic phenotype of Opa1 loss. Inhibiting fission when fusion is absent rescues FGF21 induction, oxidative stress, denervation, inflammation, and mortality, despite persistent muscle weakness.

Key findings

  • Inducible muscle-specific Opa1/Drp1 double knockout (DKO) caused progressive atrophy: gastrocnemius fiber cross-sectional area was reduced by 35%, 50%, 60%, and 45% at 70, 90, 120, and 150 days, respectively, versus controls; muscle loss then stabilized from 150 to 365 days. DKO mice also lost white adipose tissue and showed reduced absolute and mass-normalized force.
  • Mitochondria were abnormal and dysfunctional: EM showed 65% control-like mitochondria, 25% larger elongated mitochondria, and 10% with disrupted cristae or onion-like inner membrane structures; SDH staining showed larger puncta and central mitochondria-depleted areas. DKO fibers depolarized after oligomycin, with greater depolarization at 150 days than 70 days, and respiratory chain complexes I and IV were reduced while complex V slightly increased.
  • Catabolic and quality-control pathways were altered: FoxO3 and E3 ligases Atrogin1, MuRF1, SMART, and MUSA1 were induced at 70 days; autophagic flux was impaired by colchicine assay (reduced LC3 II accumulation), mitophagy was blocked by mt-mKeima, and ER stress/UPR genes ATF4, GADD34, CHOP, and GADD45 were upregulated.
  • Blocking fission in Opa1-null muscle rescued lethality: muscle and blood FGF21 peaked at 70 days and returned to control values by 365 days; GDF15 was high at 70 and 150 days but near control after one year; NCAM denervation marker appeared in 8% of fibers at 120 days and reverted by 365 days; oxidative stress was prevented, inflammation largely blunted, and the DKO survival curve was superimposed with controls.

Methods

  • Generated tamoxifen-inducible muscle-specific Opa1/Drp1 DKO mice by crossing Drp1-floxed mice with HSA-Cre-ER Opa1 transgenic mice; tamoxifen chow was given ad libitum for 5 weeks, and muscles were collected at time points from 70 to 365 days. Controls were Cre-negative littermates also receiving tamoxifen. A constitutive MLC1f-Cre Opa1/Drp1 model was attempted but yielded no homozygous DKO mice, suggesting embryonic lethality.
  • Used qPCR, immunoblotting, H&E and SDH histology, immunofluorescence, transmission EM, TMRM membrane potential measurement, mt-mKeima mitophagy assay, in vivo gastrocnemius force measurement, colchicine autophagic flux assay, OxyBlot protein carbonyl detection, blood glucose, and plasma FGF21 ELISA.
  • Statistics: means ± SEM; two-tailed Student’s t-test or two-way ANOVA with Bonferroni multiple comparison test when ANOVA was significant; significance threshold p < 0.05.

Limitations

  • The paper has no formal limitations section. It states that constitutive muscle-specific Opa1/Drp1 DKO mice were not viable and no homozygous mice were obtained, suggesting embryonic lethality and hindering further analysis.
  • Evident from the text: the study is limited to mouse models with acute tamoxifen-inducible deletion, and several mechanistic conclusions rely on transcriptional/protein correlates and pathway activation rather than direct causal rescue experiments in vivo. Human relevance is inferred from prior observations of concomitant Opa1 and Drp1 decline in aging, cachexia, and myasthenia gravis, not directly tested here.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.3390/cells8060597

Cites

42 of 42 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 56 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    The reduction of body weight in DKO mice is secondary to a significant decrease in muscle mass and white adipose tissue.

    “The reduction of body weight is secondary to a significant decrease in muscle mass (Figure 1C) and white adipose tissue (WAT) (Figure 1D).”
    Quote in the paperNot a substantial claim
  • Findingown data

    Acute ablation of Opa1 and Drp1 in adult muscle causes the accumulation of abnormal and dysfunctional mitochondria.

    “Here we show that acute ablation of Opa1 and Drp1 in adult muscle causes the accumulation of abnormal and dysfunctional mitochondria, as well as the inhibition of autophagy and mitophagy pathways.”
    Quote in the paperSubstantial claim
  • Findingown data

    Muscle loss in DKO mice stabilized from 150 to 365 days after the deletion.

    “Interestingly, muscle loss stabilized from 150 to 365 days after the deletion (Figure 1F).”
    Quote in the paperNot a substantial claim
  • Findingown data

    There was a progressive reduction of DKO gastrocnemius muscle mass.

    “There was a progressive reduction of DKO gastrocnemius muscle mass (Figure 1E)”
    Quote in the paperSubstantial claim
  • Findingown data

    Acute ablation of Opa1 and Drp1 in adult muscle causes the inhibition of autophagy and mitophagy pathways.

    “Here we show that acute ablation of Opa1 and Drp1 in adult muscle causes the accumulation of abnormal and dysfunctional mitochondria, as well as the inhibition of autophagy and mitophagy pathways.”
    Quote in the paperSubstantial claim
  • May combine two claims. 51
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Findingown data

    Extending Opa1 and Drp1 ablation in muscles for 120, 150, and 365 days leads to myofiber death and the appearance of center-nucleated fibers in approximately 6%-8% of gastrocnemius fibers.

    “However, extending Opa1 and Drp1 ablation in muscles for 120 days, 150 days, and 365 days leads to myofiber death and the appearance of center-nucleated fibers in approximately 6%–8% of gastrocnemius fibers (Figure 1G; Figure S1F, Supplementary Materials).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    H&E staining of transverse muscle sections at 70 days revealed very small fibers with no signs of inflammation, degeneration, or regeneration.

    “Muscle histology analyses by H&E staining of transverse muscle sections revealed the presence of very small fibers with no signs of inflammation, degeneration, or regeneration at 70 days (Figure 1G).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Acute ablation of Opa1 and Drp1 in adult muscle ultimately results in ER stress, muscle loss, and the reduction of force generation.

    “This ultimately results in ER stress, muscle loss, and the reduction of force generation.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mitochondria-rich oxidative fibers of soleus muscles display a more severe myopathic phenotype than gastrocnemius, with a dramatic increase of center-nucleated fibers (33%).

    “Importantly, mitochondria-rich oxidative fibers of soleus muscles display a more severe myopathic phenotype, when compared to gastrocnemius, as revealed by the dramatic increase of center-nucleated fibers (33%) (Figure S1G, Supplementary Materials).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Simultaneous inhibition of the fission protein Drp1 when Opa1 is absent alleviates FGF21 induction, oxidative stress, denervation, and inflammation.

    “However, the simultaneous inhibition of the fission protein Drp1 when Opa1 is absent alleviates FGF21 induction, oxidative stress, denervation, and inflammation rescuing the lethal phenotype of Opa1 knockout mice, despite the presence of any muscle weakness.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based).

    Findingnone given

    Simultaneous inhibition of the fission protein Drp1 when Opa1 is absent does not prevent muscle weakness.

    “However, the simultaneous inhibition of the fission protein Drp1 when Opa1 is absent alleviates FGF21 induction, oxidative stress, denervation, and inflammation rescuing the lethal phenotype of Opa1 knockout mice, despite the presence of any muscle weakness.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Western blot analyses revealed a reduction of respiratory chain complexes I and IV and a slight increase of complex V in DKO mice compared to controls.

    “Western blot analyses of the subunits of the different respiratory chain complexes revealed a reduction of complexes I and IV and a slight increase of complex V in DKO mice compared to that in controls (Figure 2E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In DKO mice, Fgf21 levels in muscle and blood peaked at 70 days, then progressively reduced and reached control values at 365 days.

    “The levels of Fgf21 in muscle (Figure 4A) and blood (Figure 4B) peaked in 70 days DKO but then were progressively reduced and then reached their control values at 365 days.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    DKO mice had metabolic alterations at 70 days, including reduced WAT, liver steatosis, and low serum glucose levels.

    “Like in Opa1-deleted mice, DKO mice had several metabolic alterations at 70 days such as reduced WAT (Figure 1D), liver steatosis (Figure S3D, Supplementary Materials) and low serum glucose levels (Figure S3E, Supplementary Materials).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    SDH staining showed bigger puncta in muscle fibers, suggesting that mitochondria are larger in DKO mice than in control muscles.

    “SDH staining showed bigger puncta in muscle fibers, suggesting that mitochondria are larger in DKO mice than in control muscles (Figure 2C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    No homozygous MLC-Drp1/Opa1 Cre-positive-floxed mice were obtained, suggesting embryonic lethality.

    “No homozygous MLC-Drp1/Opa1 Cre-positive-floxed mice were obtained, suggesting embryonic lethality (Table S3, Supplementary Materials).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In 70-day DKO muscles, AKT phosphorylation was not affected, while total AKT increased.

    “While AKT phosphorylation was not affected, the total AKT increased in 70 days DKO muscles.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    The NCAM marker of denervation started to be expressed at 120 days in 8% of DKO fibers, but reverted to control values at 365 days.

    “the NCAM marker of denervation started to be expressed at 120 days in 8% of DKO fibers, but then it reverted to the control values at 365 days (Figure 4D,E).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In DKO muscles, phospho-4EBP1 Thr37/46 and total 4EBP1 increased.

    “Phospho-4EBP1 Thr37/46 and total 4EBP1 increased”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In DKO mice, WAT was partially recovered, liver steatosis ameliorated at 120 days, and glycemia restored to normal at 150 days after tamoxifen treatment.

    “Consistent with the reduction of muscle and serum FGF21 in 150 days and 365 days DKO mice (Figure 4A,B), WAT was partially recovered (Figure 1D), liver steatosis ameliorated already at 120 days (Figure S3D), and glycemia was restored to normal levels at 150 days after tamoxifen treatment (Figure S3E, Supplementary Materials).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ultrastructural analysis by electron microscopy of 70 days DKO EDL muscles revealed a regular sarcomeric structure with the accumulation of lipid droplets.

    “Ultrastructural analysis by electron microscopy of 70 days DKO EDL muscles revealed a regular sarcomeric structure with the accumulation of lipid droplets (Figure 2B, inset b, indicated by the black arrow).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Adult DKO mice showed evident kyphosis at 90 days, partially reverted at 150 and 365 days after deletion.

    “Adult DKO mice showed an evident kyphosis at 90 days (Figure S3A, Supplementary Materials), which was partially reverted at 150 and 365 days after the deletion, keeping in line with FGF21 and GDF15 levels.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    DKO muscles display muscle loss, autophagy/mitophagy flux impairment, a mixed population of both enlarged and normal mitochondria, and mild mitochondrial dysfunction in the absence of oxidative stress.

    “Muscles display muscle loss, autophagy/mitophagy flux impairment, and a mixed population of both enlarged and normal mitochondria, as well as mild mitochondrial dysfunction in the absence of oxidative stress.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Abolishment of mitochondrial dynamics in adult muscles resulted in muscle loss and weakness.

    “The abolishment of mitochondrial dynamics in adult muscles resulted in muscle loss and weakness.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    From 150 to 365 days after deletion of Opa1 and Drp1, the transcriptional atrophy program was blunted, resulting in partial muscle mass recovery which correlates to reduced Fgf21 muscle levels, despite persistent mitochondrial dysfunction in DKO muscles.

    “However, from 150 to 365 days after the deletion of Opa1 and Drp1, the transcriptional atrophy program was blunted, resulting in a partial muscle mass recovery which correlates to reduced Fgf21 muscle levels [23], despite persistent mitochondrial dysfunction in DKO muscles.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Oost, L.J., Kustermann, M., Armani, A., Blaauw, B., and Romanello, V. (2019). Fibroblast growth factor 21 controls mitophagy and muscle mass. J. Cachex- Sarcopenia Muscle. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Muscle-specific DKO mice had a less severe phenotype than Opa1 knockout mice, which was dependent on muscle Gdf15 and Fgf21 levels.

    “Here, we showed that muscle-specific DKO mice had a less severe phenotype than Opa1 knockout mice which were dependent on muscle Gdf15 and Fgf21 levels.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Electron microscopy analyses revealed a heterogeneous mitochondrial population in DKO muscles: more than 65% resembled control mitochondria, 25% were abnormally enlarged, and 10% displayed abnormal inner organization.

    “Electron microscopy analyses revealed the presence of a heterogeneous mitochondrial population in DKO muscles. More than 65% of the observed mitochondria resembled control mitochondria, 25% were abnormally enlarged, and 10% displayed abnormal inner organization.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingreasoning

    Consistent with reduced Fgf21 induction in 150-day DKO muscles, glycemia was normalized, and WAT was partially spared after 150 days compared to 120-day DKO muscles when muscle atrophy is maximal.

    “Consistent to reduced Fgf21 induction in 150 days DKO muscles, glycemia was normalized, and WAT was partially spared after 150 days compared to that in 120 days DKO muscles when muscle atrophy is maximal.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Muscle-specific ablation of both Mfn1 and Mfn2 induces muscle atrophy and abnormal muscle growth in mice.

    “Muscle-specific ablation of both Mfn1 and Mfn2 induces muscle atrophy and abnormal muscle growth in mice [4].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [4] Chen, 2010, Mitochondrial fusion is required for mtDNA stability in skeletal muscle and tolerance of mtDNA mutations, Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Opa1-null muscles released FGF21 to mediate an integrated stress response causing oxidative stress, systemic inflammation, metabolic alterations, precocious senescence, and premature death.

    “We showed that Opa1-null muscles released FGF21 to mediate an integrated stress response which causes oxidative stress, systemic inflammation, metabolic alterations, precocious senescence of different epithelial tissues, and premature death [6].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Tezze, 2017, Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Simultaneous deletion of Opa1 and Drp1 prevented the precocious death of Opa1 knockout mice, counteracted oxidative stress, muscle and WAT loss, and prevented an inflammatory response.

    “Thus, the simultaneous deletion of Opa1 and Drp1 prevented the precocious death of Opa1 knockout mice, counteracted oxidative stress, muscle and WAT loss, and prevented an inflammatory response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Besides a loss in mass, the skeletal muscles of DKO mice also had a lower intrinsic muscle force, revealing a myopathic phenotype.

    “These results indicated that, besides a loss in mass, the skeletal muscles of DKO mice also had a lower intrinsic muscle force, revealing a myopathic phenotype (Figure 1H).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Overexpression of Opa1 protects from denervation-induced muscle loss and ameliorates muscle function in a mouse model of mitochondrial myopathy.

    “Conversely, overexpression of Opa1 protects from denervation-induced muscle loss and ameliorates muscle function in a mouse model of mitochondrial myopathy [9,10].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Civiletto, 2015, Opa1 Overexpression Ameliorates the Phenotype of Two Mitochondrial Disease Mouse Models, Cell Metab. source

      Not checked in the free run.

    • cites [10] Varanita, 2015, The Opa1-Dependent Mitochondrial Cristae Remodeling Pathway Controls Atrophic, Apoptotic, and Ischemic Tissue Damage, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The concomitant decrease of Opa1 and Drp1 also occurs in cancer cachexia and chemotherapy-induced cachexia as well as a model of myasthenia gravis.

    “Moreover, the concomitant decrease of Opa1 and Drp1 also occurs in cancer cachexia and chemotherapy-induced cachexia [15,16,17] as well as a model of myasthenia gravis [18].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [15] Barreto, 2016, Cancer and Chemotherapy Contribute to Muscle Loss by Activating Common Signaling Pathways, Front. Physiol. source

      Not checked in the free run.

    • cites [16] Brown, 2017, Mitochondrial degeneration precedes the development of muscle atrophy in progression of cancer cachexia in tumour-bearing mice, J. Cachex- Sarcopenia Muscle source

      Not checked in the free run.

    • cites [17] Grefte, 2018, Mitochondrial dynamics in cancer-induced cachexia, Biochim. Biophys. Acta Rev. Cancer source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Opa1-null mice presented a phenotype of sarcopenia and premature unhealthy aging, recapitulating 24-30 months of life in a few weeks.

    “Moreover, these mice presented a phenotype of sarcopenia and premature and unhealthy aging, in just a few weeks they recapitulated 24–30 months of life.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Tezze, 2017, Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondrial dysfunction triggers expression in muscle of FGF21 and GDF15, which positively correlate with unhealthy aging and mortality.

    “Since mitochondrial dysfunction triggers the expression in muscle of FGF21 and GDF15, which positively correlate with unhealthy aging and mortality [6,28], we measured the transcript levels of these hormones in DKO muscles.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [6] Tezze, 2017, Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence, Cell Metab. source

      Not checked in the free run.

    • cites [28] Conte, 2018, Human Aging and Longevity Are Characterized by High Levels of Mitokines, J. Gerontol. Ser. A: Boil. Sci. Med Sci. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Inhibition of mitochondrial fission in Opa1-null muscles mitigates FGF21 induction, denervation, oxidative stress, and inflammation, rescuing the lethal phenotype of Opa1 knockout mice.

    “In conclusion, inhibition of mitochondrial fission in Opa1-null muscles mitigates FGF21 induction, denervation, oxidative stress, and inflammation, rescuing the lethal phenotype of Opa1 knockout mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Muscle-specific Opa1 knockout mice display fragmented mitochondria, muscle loss, and weakness which reverberates to the whole body and leads to premature aging and then mortality.

    “Muscle-specific Opa1 knockout mice display fragmented mitochondria, muscle loss, and weakness which reverberates to the whole body and leads to premature aging and then mortality [6].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Tezze, 2017, Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The signaling pathways causing muscle loss due to combined abrogation of mitochondrial fusion and fission involved activation of the UPS and impairment of general autophagy, mitophagy flux, and activation of UPR.

    “In conclusion, the signaling pathways impinging on muscle loss due to the combined abrogation of mitochondrial fusion and fission involved the activation of the UPS and the impairment of general autophagy, as well as mitophagy flux and the activation of UPR.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Muscle-specific deletion of Opa1 triggered oxidative stress and upregulation of IL-6 and IL-1α in muscles.

    “Muscle-specific deletion of Opa1 triggered oxidative stress and upregulation of Interleukin 6 (IL-6) and Interleukin 1-alpha (IL-1α) in muscles [6].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Tezze, 2017, Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The AKT-mTOR pathway is not consistent and does not explain the observed muscle atrophy in DKO mice.

    “Thus, the AKT-mTOR pathway is not consistent and does not explain the observed muscle atrophy.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductown data

    All data were normalized to the reference gene GAPDH expression, of which abundance did not change under any of the experimental conditions.

    “All data were normalized to the reference gene GAPDH expression, of which abundance did not change under any of the experimental conditions, and plotted in arbitrary units as mean ± SEM.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Acute deletion of the fusion protein Opa1 induces muscle atrophy, systemic inflammatory response, precocious epithelial senescence, and premature death caused by muscle-dependent secretion of FGF21.

    “We have recently shown that the acute deletion of the fusion protein Opa1 induces muscle atrophy, systemic inflammatory response, precocious epithelial senescence, and premature death that are caused by muscle-dependent secretion of FGF21.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Tezze, 2017, Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Specific deletion of Opa1 in muscle leads to oxidative stress, Endoplasmic Reticulum (ER) stress, and muscle atrophy.

    “Moreover, the specific deletion of Opa1 in muscle leads to oxidative stress, Endoplasmic Reticulum (ER) stress, and muscle atrophy [6].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Tezze, 2017, Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Blocking mitochondrial dynamics in adult muscles causes WAT loss, progressive atrophy, and weakness.

    “Thus, blocking mitochondrial dynamics in adult muscles causes WAT loss, progressive atrophy, and weakness.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    No evidence of necrosis or inflammation was observed after the transfection procedure.

    “No evidence of necrosis or inflammation was observed after the transfection procedure”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Opa1-null muscles reverberate systemically, inducing metabolic alterations, inflammation, precocious senescence of different epithelial tissues and premature death via Fgf21.

    “Opa1-null muscles reverberate systemically, inducing metabolic alterations, inflammation, precocious senescence of different epithelial tissues and premature death via Fgf21 [6].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Tezze, 2017, Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The resulting mitochondrial dysfunction leads to activation of ER stress, UPR, and FGF21 pathways which further contribute to muscle atrophy.

    “Importantly, the resulting mitochondrial dysfunction leads to the activation of ER stress, UPR, and FGF21 pathways which further contribute to muscle atrophy.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Interpretationcitation

    Despite a dramatic reduction in Fgf21 in 365-day DKO muscles, lipolysis might not be completely blocked because UCP1 is induced in WAT.

    “Despite a dramatic reduction in Fgf21 in 365 days DKO muscles, lipolysis might not be completely blocked because UCP1 is induced in WAT [6].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [6] Tezze, 2017, Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In Opa1-deleted mice, chronic elevation of muscle-derived circulating Fgf21 mediated important metabolic changes, systemic inflammatory response, precocious senescence of epithelial tissues, and premature animal death.

    “In Opa1-deleted mice, chronic elevation of muscle-derived circulating Fgf21 mediated important metabolic changes, systemic inflammatory response, precocious senescence of epithelial tissues, and premature animal death [6].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [6] Tezze, 2017, Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence, Cell Metab. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Mitochondrial fusion and fission play crucial roles in the homeostatic control of muscle mass.

    “Mitochondrial fusion and fission play crucial roles in the homeostatic control of muscle mass [3].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Romanello, 2015, Mitochondrial Quality Control and Muscle Mass Maintenance, Front. Physiol.

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based). May combine two claims.

    Interpretationcitation

    The concomitant decline of mitochondrial dynamics in aging sarcopenia might be necessary to activate a mild mitochondrial dysfunction and thus mitohormesis, to promote healthy aging, while unhealthy/accelerated aging associates to unopposed mitochondrial fission.

    “Thus, the concomitant decline of mitochondrial dynamics in aging sarcopenia might be necessary to activate a mild mitochondrial dysfunction and thus mitohormesis, to promote healthy aging while unhealthy/accelerated aging associates to unopposed mitochondrial fission.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    The impossibility to maintain a healthy mitochondrial network by continuous reshaping of the organelle in DKO muscle leads to dysfunctional mitochondria which accumulate due to a block in mitophagy.

    “The impossibility to maintain a healthy mitochondrial network by the continuous reshaping of the organelle in DKO muscle leads to dysfunctional mitochondria which accumulate due to a block in mitophagy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Specific abrogation of mitochondrial dynamics in the heart leads to less severe cardiomyopathy and reverts mortality compared to unopposed fission or fusion heart-specific mouse models.

    “Like skeletal muscle, the specific abrogation of mitochondrial dynamics in the heart leads to less severe cardiomyopathy and reverts mortality in respect to unopposed fission or fusion heart-specific mice models [35].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [35] Song, 2017, Abrogating mitochondrial dynamics in mouse hearts accelerates mitochondrial senescence, Cell Metab. source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Other reports have associated high levels of circulating Fgf21 with the extension of lifespan.

    “Conversely, other reports have associated high levels of circulating Fgf21 with the extension of lifespan [34].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Zhang, 2012, The starvation hormone, fibroblast growth factor-21, extends lifespan in mice, Abstract

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    A possible explanation for the observed ultrastructural mitochondrial alterations in DKO muscles is an unbalanced Mfn1-dependent outer mitochondrial membrane fusion, while fusion of the inner membrane together with mitochondrial fission is absent.

    “A possible explanation for the observed ultrastructural mitochondria alterations is an unbalanced Mfn1-dependent outer mitochondrial membrane fusion in DKO muscles, while the fusion of the inner membrane together with mitochondrial fission is absent.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Muscle denervation, oxidative stress, and inflammation are mitigated in DKO muscles, rescuing the lethal phenotype of Opa1 knockout mice.

    “Moreover, muscle denervation, oxidative stress, and inflammation are mitigated in DKO muscles, rescuing the lethal phenotype of Opa1 knockout mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    Muscle loss in DKO mice is due to FoxO-mediated activation of the ubiquitin-proteasome system together with impairment of general autophagy and mitophagy pathways.

    “Mechanistically, muscle loss is due to FoxO-mediated activation of the ubiquitin–proteasome system together with the impairment of general autophagy and mitophagy pathways [25,31,32].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [25] Milan, 2015, Regulation of autophagy and the ubiquitin–proteasome system by the FoxO transcriptional network during muscle atrophy, Nat. Commun. source

      Not checked in the free run.

    • cites [31] Sandri, 2016, Protein breakdown in cancer cachexia, Semin. Cell Dev. Boil. source

      Not checked in the free run.

    • cites [32] Sartori, 2015, Bone and morphogenetic protein signalling and muscle mass, Curr. Opin. Clin. Nutr. Metab. Care source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Overexpression of either Atf4, Gadd45, or Fgf21 in muscles is sufficient to induce muscle atrophy.

    “In fact, the overexpression of either Atf4 [27], Gadd45 [26], or Fgf21 [23] in muscles is sufficient to induce muscle atrophy.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [27] Ebert, 2010, The Transcription Factor ATF4 Promotes Skeletal Myofiber Atrophy during Fasting, J. Clin. Endocrinol. Metab. source

      Not checked in the free run.

    • cites [26] Ebert, 2012, Stress-induced Skeletal Muscle Gadd45a Expression Reprograms Myonuclei and Causes Muscle Atrophy*, J. Boil. Chem. source

      Not checked in the free run.

    • cites [23] Oost, L.J., Kustermann, M., Armani, A., Blaauw, B., and Romanello, V. (2019). Fibroblast growth factor 21 controls mitophagy and muscle mass. J. Cachex- Sarcopenia Muscle. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    The discrepancy between inverse correlation of Fgf21 with survival and association with lifespan extension can most likely be explained by a threshold effect of Fgf21, where moderate levels result in adaptive responses to stress, while exacerbated levels are detrimental.

    “The discrepancy in the two observations can most likely be explained by the threshold effect of Fgf21, where moderate levels result in adaptive responses to stress, while exacerbated levels are detrimental to stress [28].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Conte, 2018, Human Aging and Longevity Are Characterized by High Levels of Mitokines, J. Gerontol. Ser. A: Boil. Sci. Med Sci. source

      Not checked in the free run.

55 of 55

  • The paper relies on this without support.

    The physiological role of the combined inhibition of mitochondrial fusion and fission factors in muscles has not yet been fully investigated.

    “However, the physiological role of the combined inhibition of mitochondrial fusion and fission factors in muscles has not yet been fully investigated.”

  • The paper relies on this without support.

    Skeletal muscle fibers are postmitotic cells that do not divide and cannot dilute dysfunctional mitochondria through cellular division.

    “Skeletal muscle fibers are postmitotic cells that do not divide, and as a consequence, they cannot dilute dysfunctional mitochondria through cellular division.”
2 of 2

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Authors
Romanello, V., Scalabrin, M., Albiero, M., Blaauw, B., Scorrano, L., & Sandri, M.
Affiliations
University of Padua (IT)
Corresponding author
  • Romanello, Vanina
  • Sandri, Marco
ORCID
Venue
Cells
Publisher
MDPI AG
Published
2019-06-15
Volume
8
Issue
6
Pages
597
ISSN
2073-4409 (ISSN-L)
DOI
10.3390/cells8060597
PMC
PMC6627087
OpenAlex
W2950038861
Semantic Scholar
d3210603099e4815011a830458a8cd900eba6c38
Cited by
91
References
43
Citations by year
2026: 6 · 2025: 6 · 2024: 9 · 2023: 12 · 2022: 12 · 2021: 21 · 2020: 19 · 2019: 6
FWCI
4.77
Type
journal article
Language
en
Open access
Licence
Locations
  • Cells (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
Funders
  • European Research Council (282310-MyoPHAGY)
  • AFM-Téléthon (19524)
  • Ministero dell’Istruzione, dell’Università e della Ricerca (PRIN 2010/2011)
  • Fondation Leducq (Leducq)
  • Associazione Italiana per la Ricerca sul Cancro (17388)
  • H2020 Marie Skłodowska-Curie Actions (RISE-2014 645648)
  • Fondazione Cassa di Risparmio di Padova e Rovigo (STARTING GRANT)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
OPA1, Drp1, mitochondrial fission, mitochondrial fusion, skeletal muscle atrophy, FGF21, muscle-specific knockout mice, mitophagy, autophagy, endoplasmic reticulum stress, oxidative stress, denervation, muscle inflammation, mitochondrial dysfunction
MeSH terms
Aging, Animals, Autophagy, Fibroblast Growth Factors, Mitochondria, Muscular Atrophy, Mice, Knockout, Oxidative Stress, Muscle, Skeletal, Muscle Weakness, GTP Phosphohydrolases, Ubiquitin, Dynamins, Proteasome Endopeptidase Complex, Proteolysis, Endoplasmic Reticulum Stress, Mitochondrial Dynamics, Mitophagy

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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.

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