Fibroblast growth factor 21 controls mitophagy and muscle mass
Open accessAbstract
Background: Skeletal muscle is a plastic tissue that adapts to changes in exercise, nutrition, and stress by secreting myokines and myometabolites. These muscle‐secreted factors have autocrine, paracrine, and endocrine effects, contributing to whole body homeostasis. Muscle dysfunction in aging sarcopenia, cancer cachexia, and diabetes is tightly correlated with the disruption of the physiological homeostasis at the whole body level. The expression levels of the myokine fibroblast growth factor 21 (FGF21) are very low in normal healthy muscles. However, fasting, ER stress, mitochondrial myopathies, and metabolic disorders induce its release from muscles. Although our understanding of the systemic effects of muscle‐derived FGF21 is exponentially increasing, the direct contribution of FGF21 to muscle function has not been investigated yet. Methods: Muscle‐specific FGF21 knockout mice were generated to investigate the consequences of FGF21 deletion concerning skeletal muscle mass and force. To identify the mechanisms underlying FGF21‐dependent adaptations in skeletal muscle during starvation, the study was performed on muscles collected from both fed and fasted adult mice. In vivo overexpression of FGF21 was performed in skeletal muscle to assess whether FGF21 is sufficient per se to induce muscle atrophy. Results: We show that FGF21 does not contribute to muscle homeostasis in basal conditions in terms of fibre type distribution, fibre size, and muscle force. In contrast, FGF21 is required for fasting‐induced muscle atrophy and weakness. The mass of isolated muscles from control‐fasted mice was reduced by 15–25% ( P < 0.05) compared with fed control mice. FGF21‐null muscles, however, were significantly protected from muscle loss and weakness during fasting. Such important protection is due to the maintenance of protein synthesis rate in knockout muscles during fasting compared with a 70% reduction in control‐fasted muscles ( P < 0.01), together with a significant reduction of the mitophagy flux via the regulation of the mitochondrial protein Bnip3. The contribution of FGF21 to the atrophy programme was supported by in vivo FGF21 overexpression in muscles, which was sufficient to induce autophagy and muscle loss by 15% ( P < 0.05). Bnip3 inhibition protected against FGF21‐dependent muscle wasting in adult animals ( P < 0.05). Conclusions: FGF21 is a novel player in the regulation of muscle mass that requires the mitophagy protein Bnip3.
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Written from the paper’s full text.
TL;DR
Muscle-specific FGF21 deletion does not alter basal muscle mass, fibre type, or force, but protects against fasting-induced muscle atrophy and weakness. FGF21 is required for fasting-induced loss of muscle mass and force, and its overexpression is sufficient to induce autophagy and Bnip3-dependent muscle wasting.
Key findings
- FGF21 is dispensable for basal muscle homeostasis: FGF21-null muscles showed no differences in fibre type distribution, fibre size, muscle wet weight, or force compared with controls.
- During fasting, control muscles lost 15–25% mass (P < 0.05) and protein synthesis fell by about 70% (P < 0.01); FGF21-null muscles were protected from muscle loss and weakness, maintained protein synthesis, and showed reduced mitophagy flux via Bnip3.
- In vivo FGF21 overexpression induced autophagy and decreased cross-sectional area by approximately 15% (P < 0.05); Bnip3 inhibition protected against FGF21-dependent muscle loss (P < 0.05).
Methods
- Muscle-specific FGF21 knockout mice were generated by crossing FGF21 floxed mice with MLC1f-Cre transgenic mice; Cre-negative littermates served as controls. Adult mice (3–5 months old) of the same sex, age, and body weight were studied in fed or fasted conditions (24 h for gene expression, autophagy flux, and puromycin experiments; 48 h for wet muscle weight, CSA, and force).
- Analyses included histology and fibre typing, in vivo gastrocnemius force measurements, qPCR, immunoblotting, mitochondrial isolation, autophagic/mitophagic flux with colchicine, mt-mKeima mitophagy assay, in vivo protein synthesis via SUnSET/puromycin, and in vivo FGF21 overexpression or Bnip3 RNAi by electroporation.
- Data are presented as mean ± SEM; comparisons used unpaired Student’s t-tests or two-way ANOVA with Bonferroni’s multiple comparison test, with significance set at P < 0.05.
Limitations
- The paper does not include a limitations section; stated limitations are not provided.
- Evident from the text: all experiments were performed in mice, so relevance to human sarcopenia, cachexia, or metabolic disease is not directly established.
- Evident from the text: the knockout is constitutive and muscle-specific from embryogenesis, so developmental versus adult roles of FGF21 cannot be distinguished; the fasting model also captures only acute starvation-induced atrophy.
Model-written summary. Check it against the paper before relying on it.
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Claims the paper makes
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- Findingown data
Bnip3 inhibition protects against FGF21-dependent muscle wasting in adult animals (P < 0.05).
“Bnip3 inhibition protected against FGF21‐dependent muscle wasting in adult animals (P < 0.05).”
Quote in the paperSubstantial claim - Findingown data
FGF21-null muscles were significantly protected from muscle loss and weakness during fasting.
“FGF21‐null muscles, however, were significantly protected from muscle loss and weakness during fasting.”
- Also stated in: § Muscle‐specific fibroblast growth factor 21 deletion protects against starvation‐induced muscle atrophy and weakness · boosted
“FGF21 knockout mice were completely protected from muscle loss in terms of both cross‐sectional area mean and fibre size distribution”
- Also stated in: § Muscle‐specific fibroblast growth factor 21 deletion protects against starvation‐induced muscle atrophy and weakness · plain
“in FGF21‐deficient mice, absolute muscle force in fed and starved animals was almost superimposable”
Quote in the paperSubstantial claim- Rests on an assumption: Muscle-specific deletion of FGF21 does not alter FGF21 production in other tissues or systemic FGF21 levels.
- Also stated in: § Muscle‐specific fibroblast growth factor 21 deletion protects against starvation‐induced muscle atrophy and weakness · boosted
- Findingown data
In control-fasted mice, isolated muscle mass was reduced by 15-25% (P < 0.05) compared with fed control mice.
“The mass of isolated muscles from control‐fasted mice was reduced by 15–25% (P < 0.05) compared with fed control mice.”
Quote in the paperSubstantial claim - Findingown data
FGF21-null muscles during fasting show a significant reduction of mitophagy flux.
“together with a significant reduction of the mitophagy flux via the regulation of the mitochondrial protein Bnip3”
Quote in the paperSubstantial claim - Findingown data
In FGF21-null muscles during fasting, protein synthesis rate is maintained compared with a 70% reduction in control-fasted muscles (P < 0.01).
“Such important protection is due to the maintenance of protein synthesis rate in knockout muscles during fasting compared with a 70% reduction in control‐fasted muscles (P < 0.01)”
- Also stated in: § Protein synthesis rate is maintained in fibroblast growth factor 21‐null muscles during fasting · plain
“Protein synthesis rate is maintained in fibroblast growth factor 21‐null muscles during fasting”
Quote in the paperSubstantial claim - Also stated in: § Protein synthesis rate is maintained in fibroblast growth factor 21‐null muscles during fasting · plain
- Findingown data
FGF21 does not contribute to muscle homeostasis in basal conditions in terms of fibre type distribution, fibre size, and muscle force.
“We show that FGF21 does not contribute to muscle homeostasis in basal conditions in terms of fibre type distribution, fibre size, and muscle force.”
- Also stated in: § Fibroblast growth factor 21 is dispensable for muscle mass maintenance in basal conditions · hedged
“These results indicate that FGF21 does not contribute to muscle homeostasis in basal conditions, in terms neither of fibre type nor of fibre size.”
Quote in the paperSubstantial claim - Also stated in: § Fibroblast growth factor 21 is dispensable for muscle mass maintenance in basal conditions · hedged
- Findingown data
In vivo FGF21 overexpression in muscles is sufficient to induce autophagy.
“The contribution of FGF21 to the atrophy programme was supported by in vivo FGF21 overexpression in muscles, which was sufficient to induce autophagy and muscle loss by 15% (P < 0.05).”
Quote in the paperSubstantial claim - Findingown data
In vivo FGF21 overexpression in muscles is sufficient to induce muscle loss by 15% (P < 0.05).
“The contribution of FGF21 to the atrophy programme was supported by in vivo FGF21 overexpression in muscles, which was sufficient to induce autophagy and muscle loss by 15% (P < 0.05).”
Quote in the paperSubstantial claim - Findingown data
General autophagy flux was partially reduced in starved condition in Fgf21-deleted mice.
“In contrast, the general autophagy flux was partially reduced in starved condition in Fgf21‐deleted mice (Figure 4A and 4C right panel and Supporting Information, Figure S4B).”
Quote in the paperSubstantial claim - Findingown data
No significant differences were observed in transcript levels of several autophagy-related genes between control and knockout.
“no significant differences were observed in the transcript levels of several autophagy‐related genes (Supporting Information, Figure S4A).”
Quote in the paperSubstantial claim - Findingown data
Fibre type composition, based on myosin heavy chain distribution, was unaffected in fasted knockout muscles.
“Fibre size of fasted knockout muscles was significantly higher in IIX‐IIB fibres (Figure 2F) while fibre type composition, based on myosin heavy chain distribution, was unaffected (Supporting Information, Figure S2C).”
Quote in the paperNot a substantial claim - Findingown data
Autophagic flux of the mitochondrial fraction was significantly decreased in both fed and starved conditions in FGF21 knockout mice.
“Interestingly, the autophagic flux of the mitochondrial fraction was significantly decreased in both fed and starved conditions in knockout mice (Figure 4D, 4E, and 4F and Supporting Information, Figure S4C).”
Quote in the paperSubstantial claim - Findingown data
Protection against atrophy occurs not only in GNM muscles but also in other muscles with different metabolic properties and fibre type composition such as soleus, extensor digitorum longus, and tibialis anterior.
“Interestingly, the observed protection against atrophy occurs not only in GNM muscles but also in other muscles with different metabolic properties and fibre type composition such as soleus (slow‐oxidative fibres), extensor digitorum longus, and TA (predominance of type IIB fast‐glycolytic fibres) (Supporting Information, Figure S2A).”
Quote in the paperSubstantial claim - Findingown data
Control-fasted mice were significantly weaker than fed ones.
“As expected, control‐fasted mice were significantly weaker than fed ones (Figure 2G).”
Quote in the paperSubstantial claim - Findingown data
In FGF21-deficient mice, absolute muscle force in fed and starved animals was almost superimposable.
“In contrast, in FGF21‐deficient mice, absolute muscle force in fed and starved animals was almost superimposable (Figure 2H).”
Quote in the paperSubstantial claim - Findingown data
FGF21 knockout mice were completely protected from muscle loss in terms of both cross-sectional area mean and fibre size distribution.
“Remarkably, quantification of cross‐sectional area of GNM muscles after prolonged fasting resulted in near 20% decrease in control muscles while FGF21 knockout mice were completely protected from muscle loss in terms of both cross‐sectional area mean and fibre size distribution (Figure 2D and 2E).”
Quote in the paperSubstantial claim - Findingown data
Muscle histology by H&E staining of both controls and FGF21 knockout-fasted mice showed normal structure.
“Muscle histology analyses by H&E staining of both controls and FGF21 knockout‐fasted mice showed normal structure (Figure 2B), as seen in fed mice (Figure 1C).”
Quote in the paperNot a substantial claim - Findingown data
In the absence of nutrients, protein synthesis rate of FGF21 knockout mice was similar to that in knockout fed mice.
“in the absence of nutrients, protein synthesis rate of knockout mice was similar to that in knockout fed (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
In fasted FGF21-null muscles, there were no significant differences in ubiquitin (Lys48) expression compared with control mice.
“while there were no significant differences in ubiquitin (Lys48) expression (Figure 3B, Figure 3C, and Supporting Information, Figure S3B and S3C).”
Quote in the paperSubstantial claim - Findingown data
Colchicine treatment in fasted control mice caused a significant increase of LC3II levels during fasting, indicating autophagy was ongoing in these muscles.
“As expected, colchicine treatment in fasted control mice caused a significant increase of LC3II levels during fasting, indicating that autophagy was ongoing in these muscles.”
Quote in the paperSubstantial claim - Findingown data
Epididymal fat pads were also spared in knockout mice during fasting.
“Consistent with muscle weight protection during fasting, the epididymal fat pads were also spared in knockout mice during fasting (Supporting Information, Figure S2D).”
Quote in the paperNot a substantial claim - Findingown data
Quantification of cross-sectional area of GNM muscles after prolonged fasting resulted in near 20% decrease in control muscles.
“Remarkably, quantification of cross‐sectional area of GNM muscles after prolonged fasting resulted in near 20% decrease in control muscles while FGF21 knockout mice were completely protected from muscle loss in terms of both cross‐sectional area mean and fibre size distribution (Figure 2D and 2E).”
Quote in the paperSubstantial claim - Findingown data
No significant difference in protein synthesis rate was observed in FGF21 knockout mice compared with controls in fed conditions.
“no significant differences in protein synthesis rate was observed in FGF21 knockout mice compared with controls (Figure 3A).”
Quote in the paperSubstantial claim - Findingown data
Food deprivation decreased protein synthesis rate by almost 70% in control muscles.
“Food deprivation, as expected, decreased protein synthesis rate of almost 70% in control muscles.”
Quote in the paperSubstantial claim - Findingown data
Autophagic flux in total muscle homogenates remained unchanged in fed conditions.
“Autophagic flux in total muscle homogenates remained unchanged in fed, suggesting that basal‐general autophagic flux was not altered (Figure 4A and 4C left panel and Supporting Information, Figure S4B).”
Quote in the paperSubstantial claim - Findingown data
H&E staining of transverse muscle sections detected normal muscle architecture with no signs of inflammation, degeneration, or regeneration in FGF21 null muscles.
“H&E staining of transverse muscle sections detected a normal muscle architecture with no signs of inflammation, degeneration, or regeneration (central nucleated fibres) in FGF21 null muscles (Figure 1C).”
Quote in the paperSubstantial claim - Findingown data
Wet weight of tibialis anterior, gastrocnemius, extensor digitorum longus, and soleus hindlimb muscles was similar to controls.
“The wet weight of TA, GNM, extensor digitorum longus, and soleus hindlimb muscles was similar to controls (Supporting Information, Figure S2A).”
Quote in the paperSubstantial claim - Findingown data
In fasted FGF21-null muscles, accumulation of ubiquitin (Lys63) was lower compared with control mice.
“in fasted FGF21‐null muscles, the accumulation of ubiquitin (Lys63) was lower comparing knockout with control mice”
Quote in the paperSubstantial claim - Findingown data
mt-mKeima was not able to reveal differences in basal mitophagy flux between knockout and control muscles.
“Although mt‐mKeima was not able to reveal differences in the basal mitophagy flux between knockout and control muscles”
Quote in the paperNot a substantial claim - Findingown data
Expression levels of Atrogin1, MuRF1, SMART, MUSA1, Fbxo31, Itch, and Trim37 were the same in control and knockout muscles in both fed and fasting state.
“The expression levels of the well‐known muscle‐specific E3 ubiquitin ligases Atrogin1 and MuRF1, as well as the recently discovered SMART, MUSA1, Fbxo31, Itch, and Trim37,37 were the same in control and knockout muscles in both fed and fasting state”
Quote in the paperSubstantial claim - Findingown data
Fasting increased both Lys48 and Lys63 polyubiquitinated proteins in control mice.
“As expected, fasting resulted in an increase of both Lys48 and Lys63 polyubiquitinated proteins in control mice.”
Quote in the paperSubstantial claim - Findingown data
Fibre size of fasted knockout muscles was significantly higher in IIX-IIB fibres.
“Fibre size of fasted knockout muscles was significantly higher in IIX‐IIB fibres (Figure 2F) while fibre type composition, based on myosin heavy chain distribution, was unaffected (Supporting Information, Figure S2C).”
Quote in the paperNot a substantial claim - Findingown data
Expression of FGF21 receptors FGFR1, 1b, and 1c but not FGFR4 increases in muscles during starvation.
“Accordingly, the expression of the FGF21 receptors: FGFR1, 1b, and 1c but not FGFR4 increase in muscles during starvation (Supporting Information, Figure S2B).”
Quote in the paperNot a substantial claim - Findingown data
PAS staining showed increased glycogen content and thereby energy storage in knockout animals versus control during starvation.
“PAS staining showed increased glycogen content and thereby energy storage in knockout animals vs. control during starvation (Figure 2C).”
Quote in the paperNot a substantial claim - Findingown data
Mitochondrial content, revealed by SDH staining, was higher in both fed and fasting FGF21-null muscles compared with controls.
“mitochondrial content, revealed by SDH staining, was higher in both fed and fasting FGF21‐null muscles when compared with controls (Figure 4H).”
Quote in the paperSubstantial claim - Findingown data
Quantitative analysis of myosin heavy chain distribution and fibre size measurements of GNM muscles did not show any difference between control and FGF21 knockout mice.
“Quantitative analysis of myosin heavy chain distribution (Figure 1D) and of fibre size measurements of GNM muscles (Figure 1E and Figure 1F) did not show any difference between control and FGF21 knockout mice.”
Quote in the paperSubstantial claim - Findingown data
Distribution of glycogen stores revealed by PAS staining was unaffected by FGF21 deletion.
“The distribution of glycogen stores revealed by PAS staining was unaffected by FGF21 deletion (Figure 1C).”
Quote in the paperNot a substantial claim - Findingown data
Autophagosome quantification was significantly higher in FGF21-expressing fibres than in mock-transfected fibres.
“Interestingly, autophagosome quantification was significantly higher in FGF21‐expressing fibres than in mock‐transfected fibres (Figure 5B).”
Quote in the paperSubstantial claim - Findingown data
Mitochondrial mass, revealed by Tom20 immunoblot, was significantly increased in FGF21-deleted muscles.
“The reduction of mitophagy flux in the absence of FGF21 was further confirmed by significant increase in mitochondrial mass, revealed by Tom20 immunoblot (Figure 4I and Supporting Information, Figure S4D)”
Quote in the paperSubstantial claim - Findingown data
Fibre size distribution shifted towards a smaller fibre size with FGF21 overexpression.
“Accordingly, fibre size distribution shifted towards a smaller fibre size (Figure 5D).”
Quote in the paperSubstantial claim - Findingown data
Inhibition of Bnip3 resulted in significant protection from FGF21-induced muscle loss.
“Inhibition of Bnip3 resulted in a significant protection from FGF21‐induced muscle loss (Figure 5E)”
- Also stated in: § Discussion · plain
“Inhibition of the mitophagy factor Bnip3, in vivo, by RNAi, was sufficient to reduce FGF21‐dependent muscle atrophy.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Findingnone given
FGF21 and FGFRs gene expression levels increase in muscles in response to fasting in control muscles.
“FGF21 and FGFRs gene expression levels increase in muscles in response to fasting in control muscles.”
Quote in the paperSubstantial claim - Findingown data
FGF21 overexpression results in approximately 15% decrease in cross-sectional area of transfected fibres compared with surrounding non-transfected fibres.
“In contrast, FGF21 overexpression results in approximately 15% decrease in cross‐sectional area of transfected fibres compared with the surrounding non‐transfected fibres (Figure 5C).”
Quote in the paperSubstantial claim - Findingown data
Levels of the mitophagy protein Bnip3 were decreased in FGF21 knockout muscles.
“and by decreased levels of the mitophagy protein Bnip3 (Figure 4J and Supporting Information, Figure S4E).”
Quote in the paperSubstantial claim - Findingown data
Transfection of the mock vector does not alter myofiber size.
“Transfection of the mock vector does not alter myofiber size (Figure 5C).”
Quote in the paperSubstantial claim - Premisereasoning
Circulating FGF21 is predominantly produced and released by the liver.
“In skeletal muscle, FGF21 expression, in healthy conditions, is almost undetectable, and therefore, the circulating FGF21 is predominantly produced and released by the liver.6, 12”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [6] Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K. FGF21 is an Akt‐regulated myokine. FEBS Lett 2008; 582: 3805– 3810. 18948104 PMC2604129 source
Not checked in the free run.
- cites [12] Markan KR, Naber MC, Ameka MK, Anderegg MD, Mangelsdorf DJ, Kliewer SA, et al. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 2014; 63: 4057– 4063. 25008183 PMC4238010 source
Not checked in the free run.
- Interpretationown data
The reduction of mitophagy flux in FGF21-null muscles during fasting is via regulation of the mitochondrial protein Bnip3.
“together with a significant reduction of the mitophagy flux via the regulation of the mitochondrial protein Bnip3”
Quote in the paperSubstantial claim - Interpretationown data
FGF21 is required for fasting-induced muscle atrophy and weakness.
“In contrast, FGF21 is required for fasting‐induced muscle atrophy and weakness.”
- Also stated in: § Muscle‐specific fibroblast growth factor 21 deletion protects against starvation‐induced muscle atrophy and weakness · hedged
“Altogether, these results suggest that increased expression of FGF21 during fasting is required for muscle atrophy and weakness.”
Quote in the paperSubstantial claim- Rests on an assumption: Muscle-specific deletion of FGF21 does not alter FGF21 production in other tissues or systemic FGF21 levels.
- Also stated in: § Muscle‐specific fibroblast growth factor 21 deletion protects against starvation‐induced muscle atrophy and weakness · hedged
- Premisecitation
In healthy skeletal muscle, FGF21 expression is almost undetectable.
“In skeletal muscle, FGF21 expression, in healthy conditions, is almost undetectable, and therefore, the circulating FGF21 is predominantly produced and released by the liver.6, 12”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [6] Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K. FGF21 is an Akt‐regulated myokine. FEBS Lett 2008; 582: 3805– 3810. 18948104 PMC2604129 source
Not checked in the free run.
- cites [12] Markan KR, Naber MC, Ameka MK, Anderegg MD, Mangelsdorf DJ, Kliewer SA, et al. Circulating FGF21 is liver derived and enhances glucose uptake during refeeding and overfeeding. Diabetes 2014; 63: 4057– 4063. 25008183 PMC4238010 source
Not checked in the free run.
- Study design and conductown data
q-PCR revealed efficient reduction of FGF21 transcript levels.
“Quantitative real‐time PCR (q‐PCR) also revealed the efficient reduction of FGF21 transcript levels (Figure 1B).”
Quote in the paperSubstantial claim - Premisecitation
In a muscle-specific OPA1 knockout animal model, the contribution of skeletal muscle to circulating FGF21 is predominant.
“Moreover, we and others recently demonstrated that in a muscle‐specific OPA1 knockout animal model, characterized by mitochondrial dysfunction and by extensive muscle loss, the contribution of skeletal muscle to circulating FGF21 was predominant.15, 16, 18”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [15] Pereira RO, Tadinada SM, Zasadny FM, Oliveira KJ, Pires KMP, Olvera A, et al. OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance. EMBO J 2017; 36: 2126– 2145. 28607005 PMC5510002 source
Not checked in the free run.
- cites [16] Rodriguez‐Nuevo A, Diaz-Ramos A, Noguera E, Diaz‐Saez F, Duran X, Munoz JP, et al. Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency. EMBO J 2018; 37: e96553. 29632021 PMC5978453 source
Not checked in the free run.
- cites [18] Tezze C, Romanello V, Desbats MA, Fadini GP, Albiero M, Favaro G, et al. Age‐associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and Epithelial Senescence. Cell Metab 2017; 25: 1374– 1389 e6. 28552492 PMC5462533 source
Not checked in the free run.
- Premisecitation
A positive correlation of serum FGF21 levels and aging-sarcopenia has been found.
“In agreement, a positive correlation of serum FGF21 levels and aging‐sarcopenia has been found.18, 21”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [18] Tezze C, Romanello V, Desbats MA, Fadini GP, Albiero M, Favaro G, et al. Age‐associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and Epithelial Senescence. Cell Metab 2017; 25: 1374– 1389 e6. 28552492 PMC5462533 source
Not checked in the free run.
- cites [21] Hanks LJ, Gutierrez OM, Bamman MM, Ashraf A, McCormick KL, Casazza K. et al. Circulating levels of fibroblast growth factor‐21 increase with age independently of body composition indices among healthy individuals. J Clin Transl Endocrinol 2015; 2: 77– 82. 26042208 PMC4450097 source
Not checked in the free run.
- Study design and conductown data
Effective ablation of the floxed sequence from genomic DNA extracted from skeletal muscle was confirmed by PCR analysis.
“The effective ablation of the floxed sequence from genomic DNA extracted from skeletal muscle was confirmed by PCR analysis (Figure 1A).”
Quote in the paperSubstantial claim - Premisecitation
In the muscle-specific OPA1 knockout model, FGF21 secreted from muscles mediates an integrated stress response causing systemic cell non-autonomous effects such as inflammation, metabolic alterations, and precocious senescence.
“In this model, FGF21 secreted from muscles mediates an integrated stress response that caused several systemic cell non‐autonomous effects such as inflammation, metabolic alterations, and precocious senescence.18”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Tezze C, Romanello V, Desbats MA, Fadini GP, Albiero M, Favaro G, et al. Age‐associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and Epithelial Senescence. Cell Metab 2017; 25: 1374– 1389 e6. 28552492 PMC5462533 source
Not checked in the free run.
- Interpretationown data
Bnip3 is required for FGF21-dependent muscle atrophy.
“suggesting that Bnip3 is required for FGF21‐dependent muscle atrophy.”
- Also stated in: § Discussion · plain
“Thus, Bnip3 is a key factor in muscle loss induced by FGF21.”
Quote in the paperSubstantial claim - Also stated in: § Discussion · plain
- Interpretationown data
This is the first study demonstrating that, in mammalian skeletal muscle, FGF21 is involved in the removal of damaged mitochondria through mitophagy.
“To our knowledge, this is the first study demonstrating that, in mammalian skeletal muscle, FGF21 is involved in the removal of damaged mitochondria through mitophagy.”
Quote in the paperSubstantial claim - Interpretationown data
FGF21 is a novel player in the regulation of muscle mass.
“Here, we identify FGF21 as a novel player in the regulation of muscle mass.”
Quote in the paperSubstantial claim - Interpretationown data
The current study elucidates a novel role for FGF21 in the control of skeletal muscle mass through the regulation of the anabolic/catabolic balance.
“In summary, the current study elucidates by using gain and loss of function approaches, a novel role for FGF21 in the control of skeletal muscle mass through the regulation of the anabolic/catabolic balance.”
Quote in the paperSubstantial claim - Interpretationown data
FGF21 is required for fasting-dependent muscle mass and force loss.
“Our data indicate that FGF21 is required for fasting‐dependent muscle mass and force loss.”
Quote in the paperSubstantial claim - Premisecitation
FGF21 is a stress-induced myokine released under conditions of starvation, ER stress, mitochondrial dysfunction, obesity, mitochondrial myopathies, and aging.
“(ii) FGF21 is a stress‐induced myokine, which is released under conditions of starvation, ER stress, mitochondrial dysfunction, obesity, mitochondrial myopathies, and aging.6, 13, 14, 15, 16, 17, 18”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [6] Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K. FGF21 is an Akt‐regulated myokine. FEBS Lett 2008; 582: 3805– 3810. 18948104 PMC2604129 source
Not checked in the free run.
- cites [13] Keipert S, Ost M, Johann K, Imber F, Jastroch M, van Schothorst EM, et al. Skeletal muscle mitochondrial uncoupling drives endocrine cross‐talk through the induction of FGF21 as a myokine. Am J Physiol Endocrinol Metab 2014; 306: E469– E482. 24347058 source
Not checked in the free run.
- cites [14] Ost M, Coleman V, Voigt A, van Schothorst EM, Keipert S, van der Stelt I, et al. Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action. Mol Metab 2016; 5: 79– 90. 26909316 PMC4735627 source
Not checked in the free run.
- Premisecitation
Serum FGF21 levels positively correlate with aging sarcopenia.
“Indeed, serum FGF21 levels positively correlated with aging sarcopenia.18, 21”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [18] Tezze C, Romanello V, Desbats MA, Fadini GP, Albiero M, Favaro G, et al. Age‐associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and Epithelial Senescence. Cell Metab 2017; 25: 1374– 1389 e6. 28552492 PMC5462533 source
Not checked in the free run.
- cites [21] Hanks LJ, Gutierrez OM, Bamman MM, Ashraf A, McCormick KL, Casazza K. et al. Circulating levels of fibroblast growth factor‐21 increase with age independently of body composition indices among healthy individuals. J Clin Transl Endocrinol 2015; 2: 77– 82. 26042208 PMC4450097 source
Not checked in the free run.
- Interpretationown data
Muscle mass and force sparing during fasting in knockout mice can be explained by the maintenance of protein synthesis rate.
“Muscle mass and force sparing during fasting in knockout mice can be explained by the maintenance of protein synthesis rate.”
Quote in the paperSubstantial claim
- May combine two claims. 12
- Classified as probably not a substantial claim. 11
May combine two claims.
Findingown dataSpecific force showed no significant differences in any of the conditions studied, indicating no myopathy in the absence of FGF21.
“When we analysed the force normalized for muscle mass, named specific force, no significant differences were detected in any of the conditions studied, indicating that there is no myopathy in the absence of FGF21 (Supporting Information, Figure S2E).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataIn FGF21-null mice during fasting, FGFR1c is slightly lower while β-Klotho expression is significantly reduced.
“Of note, in FGF21‐null mice during fasting, FGFR1c is slightly lower while β‐Klotho expression is significantly reduced (Supporting Information, Figure S2B).”
Quote in the paperNot a substantial claimMay combine two claims.
FindingreasoningIn fed condition, loss of FGF21 in skeletal muscle does not induce any change in muscle mass, force, and fibre type.
“In fed condition, loss of FGF21 in skeletal muscle does not induce any change in muscle mass, force, and fibre type”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationreasoningFGF21 is a novel player in the regulation of muscle mass that requires the mitophagy protein Bnip3.
“FGF21 is a novel player in the regulation of muscle mass that requires the mitophagy protein Bnip3.”
Quote in the paperSubstantial claim- Rests on an assumption: Muscle-specific deletion of FGF21 does not alter FGF21 production in other tissues or systemic FGF21 levels.
May combine two claims.
PremisecitationMuscle-dependent systemic release of FGF21 increases with starvation, endoplasmic reticulum stress, mitochondrial dysfunction, obesity, mitochondrial myopathies, and aging.
“In contrast, muscle‐dependent systemic release of FGF21 increases with starvation, endoplasmic reticulum stress, mitochondrial dysfunction, obesity, mitochondrial myopathies, and aging.6, 13, 14, 15, 16, 17, 18, 19”
Quote in the paperSubstantial claim0 of 8 sources checked- cites [6] Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K. FGF21 is an Akt‐regulated myokine. FEBS Lett 2008; 582: 3805– 3810. 18948104 PMC2604129 source
Not checked in the free run.
- cites [13] Keipert S, Ost M, Johann K, Imber F, Jastroch M, van Schothorst EM, et al. Skeletal muscle mitochondrial uncoupling drives endocrine cross‐talk through the induction of FGF21 as a myokine. Am J Physiol Endocrinol Metab 2014; 306: E469– E482. 24347058 source
Not checked in the free run.
- cites [14] Ost M, Coleman V, Voigt A, van Schothorst EM, Keipert S, van der Stelt I, et al. Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action. Mol Metab 2016; 5: 79– 90. 26909316 PMC4735627 source
Not checked in the free run.
- cites [15] Pereira RO, Tadinada SM, Zasadny FM, Oliveira KJ, Pires KMP, Olvera A, et al. OPA1 deficiency promotes secretion of FGF21 from muscle that prevents obesity and insulin resistance. EMBO J 2017; 36: 2126– 2145. 28607005 PMC5510002 source
Not checked in the free run.
- cites [16] Rodriguez‐Nuevo A, Diaz-Ramos A, Noguera E, Diaz‐Saez F, Duran X, Munoz JP, et al. Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency. EMBO J 2018; 37: e96553. 29632021 PMC5978453 source
Not checked in the free run.
- cites [17] Suomalainen A, Elo JM, Pietilainen KH, Hakonen AH, Sevastianova K, Korpela M, et al. FGF‐21 as a biomarker for muscle‐manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 2011; 10: 806– 818. 21820356 PMC7568343 source
Not checked in the free run.
- cites [18] Tezze C, Romanello V, Desbats MA, Fadini GP, Albiero M, Favaro G, et al. Age‐associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and Epithelial Senescence. Cell Metab 2017; 25: 1374– 1389 e6. 28552492 PMC5462533 source
Not checked in the free run.
- cites [19] Vandanmagsar B, Warfel JD, Wicks SE, Ghosh S, Salbaum JM, Burk D, et al. Impaired mitochondrial fat oxidation induces FGF21 in muscle. Cell Rep 2016; 15: 1686– 1699. 27184848 PMC4880522 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFGF21 mainly binds to FGFR1 (FGFR1b and FGFR1c) and to a lower extent to FGFR4.
“FGF21 mainly binds to FGFR1 (FGFR1b and FGFR1c) and to a lower extent to FGFR4.33”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [33] Staiger H, Keuper M, Berti L, Hrabe de Angelis M, Haring HU. Fibroblast growth factor 21‐metabolic role in mice and men. Endocr Rev 2017; 38: 468– 488. 28938407 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationSkeletal muscle is not only a producer but also a target of FGF21 because it expresses the cofactor β-klotho and the FGFRs.
“Recent studies reported that skeletal muscle is not only a producer but also a target of FGF21 because it expresses the cofactor β‐klotho and the FGFRs.6, 13, 14, 17, 18, 19”
Quote in the paperSubstantial claim0 of 6 sources checked- cites [6] Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K. FGF21 is an Akt‐regulated myokine. FEBS Lett 2008; 582: 3805– 3810. 18948104 PMC2604129 source
Not checked in the free run.
- cites [13] Keipert S, Ost M, Johann K, Imber F, Jastroch M, van Schothorst EM, et al. Skeletal muscle mitochondrial uncoupling drives endocrine cross‐talk through the induction of FGF21 as a myokine. Am J Physiol Endocrinol Metab 2014; 306: E469– E482. 24347058 source
Not checked in the free run.
- cites [14] Ost M, Coleman V, Voigt A, van Schothorst EM, Keipert S, van der Stelt I, et al. Muscle mitochondrial stress adaptation operates independently of endogenous FGF21 action. Mol Metab 2016; 5: 79– 90. 26909316 PMC4735627 source
Not checked in the free run.
- cites [17] Suomalainen A, Elo JM, Pietilainen KH, Hakonen AH, Sevastianova K, Korpela M, et al. FGF‐21 as a biomarker for muscle‐manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 2011; 10: 806– 818. 21820356 PMC7568343 source
Not checked in the free run.
- cites [18] Tezze C, Romanello V, Desbats MA, Fadini GP, Albiero M, Favaro G, et al. Age‐associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and Epithelial Senescence. Cell Metab 2017; 25: 1374– 1389 e6. 28552492 PMC5462533 source
Not checked in the free run.
- cites [19] Vandanmagsar B, Warfel JD, Wicks SE, Ghosh S, Salbaum JM, Burk D, et al. Impaired mitochondrial fat oxidation induces FGF21 in muscle. Cell Rep 2016; 15: 1686– 1699. 27184848 PMC4880522 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationFGF21 is expressed and released into the general circulation by several tissues such as the liver, white adipose tissue, brown adipose tissue, and the heart.
“The metabolic regulator FGF21 is expressed and released into the general circulation by several tissues such as the liver, WAT, BAT, and the heart.7, 8, 9, 10, 11”
Quote in the paperNot a substantial claim0 of 5 sources checked- cites [7] Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos‐Flier E. Hepatic fibroblast growth factor 21 is regulated by PPARα and is a key mediator of hepatic lipid metabolism in ketotic states. Cell Metab 2007; 5: 426– 437. 17550778 source
Not checked in the free run.
- cites [8] Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, et al. Endocrine regulation of the fasting response by PPARα‐mediated induction of fibroblast growth factor 21. Cell Metab 2007; 5: 415– 425. 17550777 source
Not checked in the free run.
- cites [9] Patel V, Adya R, Chen J, Ramanjaneya M, Bari MF, Bhudia SK, et al. Novel insights into the cardio‐protective effects of FGF21 in lean and obese rat hearts. PLoS One 2014; 9: e87102. 24498293 PMC3911936 source
Not checked in the free run.
- cites [10] Muise ES, Azzolina B, Kuo DW, El‐Sherbeini M, Tan Y, Yuan X, et al. Adipose fibroblast growth factor 21 is up‐regulated by peroxisome proliferator‐activated receptor gamma and altered metabolic states. Mol Pharmacol 2008; 74: 403– 412. 18467542 source
Not checked in the free run.
- cites [11] Hondares E, Iglesias R, Giralt A, Gonzalez FJ, Giralt M, Mampel T, et al. Thermogenic activation induces FGF21 expression and release in brown adipose tissue. J Biol Chem 2011; 286: 12983– 12990. 21317437 PMC3075644 source
Not checked in the free run.
May combine two claims.
Study design and conductown dataFGF21 muscle-specific knockout mice were born at the expected Mendelian ratio, were viable, and had a normal growth curve compared with age-matched control littermates.
“The resulting FGF21 muscle‐specific knockout mice (hereafter referred to as FGF21−/−) were born at the expected Mendelian ratio, were viable, and had a normal growth curve compared with age‐matched control littermates (FGF21f/f) (Supporting Information, Figure S1).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationFGF21 deletion in OPA1 knockout muscles improved almost all systemic effects, while there was only partial sparing of muscle mass.
“Importantly, FGF21 deletion in OPA1 knockout muscles improved almost all systemic effects, while there was only a partial sparing of muscle mass.18”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [18] Tezze C, Romanello V, Desbats MA, Fadini GP, Albiero M, Favaro G, et al. Age‐associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and Epithelial Senescence. Cell Metab 2017; 25: 1374– 1389 e6. 28552492 PMC5462533 source
Not checked in the free run.
May combine two claims.
Interpretationown dataIn the absence of nutrients, protection from fasting-induced muscle loss in FGF21 null muscles depends on maintenance of protein synthesis rate together with a reduction of autophagy-dependent degradation, while UPS activation is not altered.
“Collectively, these results suggest that in the absence of nutrients, the protection from fasting‐induced muscle loss in FGF21 null muscles depend on the maintenance of protein synthesis rate together with a reduction of the autophagy‐dependent degradation while the UPS activation is not altered.”
Quote in the paperSubstantial claim- Rests on an assumption: Ubiquitin (Lys63) is important in the recognition of autophagy cargo.
Classified as probably not a substantial claim.
PremisecitationStarvation is one of the stress conditions known to induce FGF21 expression in the liver, white adipose tissue, and skeletal muscle.
“Starvation is one of the stress conditions known to induce FGF21 expression in the liver,8, 32 WAT,10 and skeletal muscle (Figure 2A).6”
Quote in the paperSubstantial claim0 of 4 sources checked- cites [8] Inagaki T, Dutchak P, Zhao G, Ding X, Gautron L, Parameswara V, et al. Endocrine regulation of the fasting response by PPARα‐mediated induction of fibroblast growth factor 21. Cell Metab 2007; 5: 415– 425. 17550777 source
Not checked in the free run.
- cites [32] Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, et al. FGF21 induces PGC‐1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proc Natl Acad Sci U S A 2009; 106: 10853– 10858. 19541642 PMC2705613 source
Not checked in the free run.
- cites [10] Muise ES, Azzolina B, Kuo DW, El‐Sherbeini M, Tan Y, Yuan X, et al. Adipose fibroblast growth factor 21 is up‐regulated by peroxisome proliferator‐activated receptor gamma and altered metabolic states. Mol Pharmacol 2008; 74: 403– 412. 18467542 source
Not checked in the free run.
- cites [6] Izumiya Y, Bina HA, Ouchi N, Akasaki Y, Kharitonenkov A, Walsh K. FGF21 is an Akt‐regulated myokine. FEBS Lett 2008; 582: 3805– 3810. 18948104 PMC2604129 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationInjecting mice daily with exogenous FGF19 increased skeletal muscle mass and strength.
“Injecting mice daily with exogenous FGF19, a closely related endocrine FGF member produced in the gut, increased skeletal muscle mass and strength.”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [22] Benoit B, Meugnier E, Castelli M, Chanon S, Vieille‐Marchiset A, Durand C, et al. Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice. Nat Med 2017; 23: 990– 996. 28650457 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationFGF21 is a stress-induced myokine proposed as a specific serum biomarker of muscle-specific mitochondrial disorders.
“Moreover, FGF21 is a stress‐induced myokine that has been proposed as a specific serum biomarker of muscle‐specific mitochondrial disorders.17, 20”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [17] Suomalainen A, Elo JM, Pietilainen KH, Hakonen AH, Sevastianova K, Korpela M, et al. FGF‐21 as a biomarker for muscle‐manifesting mitochondrial respiratory chain deficiencies: a diagnostic study. Lancet Neurol 2011; 10: 806– 818. 21820356 PMC7568343 source
Not checked in the free run.
- cites [20] Lehtonen JM, Forsstrom S, Bottani E, Viscomi C, Baris OR, Isoniemi H, et al. FGF21 is a biomarker for mitochondrial translation and mtDNA maintenance disorders. Neurology 2016; 87: 2290– 2299. 27794108 PMC5270510 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationSkeletal muscle hypertrophy effects were not elicited by administering FGF21.
“Remarkably, the skeletal muscle hypertrophy effects were not elicited by administrating FGF21.22”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [22] Benoit B, Meugnier E, Castelli M, Chanon S, Vieille‐Marchiset A, Durand C, et al. Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice. Nat Med 2017; 23: 990– 996. 28650457 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe metabolic adaptation mediated by FGF21 during fasting in the liver and white adipose tissue is known to increase lipolysis and hepatic ketogenesis.
“The metabolic adaptation mediated by FGF21 during fasting in the liver and WAT is known to increase lipolysis and hepatic ketogenesis.34”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [34] Fisher FM, Maratos‐Flier E. Understanding the physiology of FGF21. Annu Rev Physiol 2016; 78: 223– 241. 26654352 source
Not checked in the free run.
May combine two claims.
Interpretationown dataFGF21 controls more specifically the mitophagic flux rather than the general autophagy, which was partially reduced in knockout mice during fasting.
“In summary, FGF21 controls more specifically the mitophagic flux rather than the general autophagy, which was partially reduced in knockout mice during fasting.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataMuscle protection in fasted FGF21 knockout mice does not depend on regulation of UPS, but depends on regulation of autophagy and more specifically mitophagy pathways.
“Our findings indicate that muscle protection in fasted FGF21 knockout mice does not depend on the regulation of UPS, but it rather depends on the regulation of autophagy and, more specifically, mitophagy pathways.”
Quote in the paperSubstantial claim- Rests on an assumption: Ubiquitin (Lys63) is important in the recognition of autophagy cargo.
Classified as probably not a substantial claim.
PremisecitationMuscle loss requires activation of a transcription-dependent programme controlled by atrophy-related genes (atrogenes).
“Because muscle loss requires the activation of transcription‐dependent programme controlled by the regulation of a subset of genes named atrophy‐related genes or atrogenes,36 we monitored several atrogenes mRNAs”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [36] Cohen S, Nathan JA, Goldberg AL. Muscle wasting in disease: molecular mechanisms and promising therapies. Nat Rev Drug Discov 2015; 14: 58– 74. 25549588 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationMitophagy, the selective degradation of dysfunctional mitochondria, is critical for the maintenance of muscle mass.
“Because mitophagy, the selective degradation of dysfunctional mitochondria, is critical for the maintenance of muscle mass,2 we isolated mitochondria”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Romanello V, Sandri M. Mitochondrial quality control and muscle mass maintenance. Front Physiol 2015; 6: 422. 26793123 PMC4709858
Not checked in the free run.
May combine two claims.
PremisecitationBnip3 inhibition reduces autophagosome formation and protects against muscle loss during atrophy.
“we already demonstrated that Bnip3 inhibition reduces autophagosome formation and protects against muscle loss during atrophy,25, 38”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [25] Romanello V, Guadagnin E, Gomes L, Roder I, Sandri C, Petersen Y, et al. Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J 2010; 29: 1774– 1785. 20400940 PMC2876965 source
Not checked in the free run.
- cites [38] Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 2007; 6: 458– 471. 18054315 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationThe autophagy lysosomal system is essential for muscle homeostasis.
“we focused in the other muscle major degradative pathway, the autophagy lysosomal system, which is essential for muscle homeostasis.38, 39”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [38] Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 2007; 6: 458– 471. 18054315 source
Not checked in the free run.
- cites [39] Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, et al. Autophagy is required to maintain muscle mass. Cell Metab 2009; 10: 507– 515. 19945408 source
Not checked in the free run.
The paper relies on this without support.
Muscle-specific deletion of FGF21 does not alter FGF21 production in other tissues or systemic FGF21 levels.
“To generate constitutive muscle‐specific FGF21 knockout animals, mice bearing FGF21 floxed alleles (FGF211f/f) (The Jackson Laboratory) were crossed with transgenic mice expressing Cre under the control of a Myosin Light Chain 1 fast promoter.23 Cre‐negative littermates were used as controls.”
The authors state this as an assumption.
The functional role of FGF21 in skeletal muscle homeostasis is not clear.
“What is not clear is which is the functional role of FGF21 in the context of skeletal muscle homeostasis.”
The paper relies on this without support.
Increased protein synthesis without acting on protein breakdown may not be sufficient to prevent muscle atrophy and weakness during starvation, because the co-ordination of these two processes determines protein turnover.
“The increased protein synthesis without acting on protein breakdown may not be sufficient to prevent muscle atrophy and weakness during starvation, because the co‐ordination of these two processes determines protein turnover.”
The paper relies on this without support.
Ubiquitin (Lys63) is important in the recognition of autophagy cargo.
“as ubiquitin (Lys63) is important in the recognition of autophagy cargo”
The paper relies on this without support.
All conditions with elevated FGF21 (obesity, diabetes, mitochondrial diseases, etc.) have in common muscle atrophy.
“Interestingly, all these conditions have in common muscle atrophy.”
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?
FGF21 is sufficient and required to induce muscle loss.
“This finding is in contrast with another report showing that FGF21 is sufficient and required to induce muscle loss27.”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [27]
FGF21 promotes muscle loss by increasing Bnip3-dependent mitophagy.
“For instance, the cytokine FGF21 promotes muscle loss by increasing Bnip3-dependent mitophagy27”
From Mechanisms of muscle atrophy and hypertrophy: implications in health and disease (2021) · cites this paper as [27]
FGF21 overexpression in skeletal muscle induces BNIP3-dependent mitophagy and muscle atrophy.
“Of note, FGF21 overexpression in skeletal muscle induces BNIP3-dependent mitophagy and muscle atrophy [212].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [212]
Decrease of FGF21 levels correlated with a partial muscle mass recovery.
“Notably, the decrease of FGF21 levels correlated with a partial muscle mass recovery [212].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [212]
Transient inhibition of BNIP3 in skeletal muscle partially protects from muscle loss induced by fasting, FoxO3, and FGF21 overexpression.
“In agreement, transient inhibition of BNIP3 in skeletal muscle partially protects from muscle loss induced by fasting, FoxO3, and FGF21 overexpression [15, 152, 212].”
From The connection between the dynamic remodeling of the mitochondrial network and the regulation of muscle mass (2021) · cites this paper as [212]
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.”
From Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles (2019) · cites this paper as [23]
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.”
From Inhibition of the Fission Machinery Mitigates OPA1 Impairment in Adult Skeletal Muscles (2019) · cites this paper as [23]
FGF21 may exert its effects on muscle mass via regulation of the mitophagy protein Bnip3.
“It has been reported that FGF21 may exert its effects on muscle mass via regulation of the mitophagy protein Bnip3 [101].”
From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [101]
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.
Mitochondrial isolation is attributed to different muscles
MinorThe mitochondrial-isolation method specifies quadriceps muscles, but the Figure 4 caption describes the isolated mitochondria used for its immunoblots as coming from gastrocnemius muscles.
“Mitochondria from quadriceps muscles of the indicated genotypes were isolated as described18 and were then probed with the indicated antibodies by immunoblotting.”
“(D–E) Representative immunoblot images of mitochondria isolated from GNM muscles after colchicine treatment probed with anti‐LC3 antibody in fed (D) and in fasting conditions.”
Knockout force curve is assigned to both Figure 2G and Figure 2H
MinorThe results cite Figure 2H for force in knockout mice, whereas the Figure 2 caption places the knockout force curve in the right panel of Figure 2G.
“In contrast, in FGF21‐deficient mice, absolute muscle force in fed and starved animals was almost superimposable (Figure 2H).”
“(G) Force measurements performed in vivo on gastrocnemius showed that FGF21−/− muscles preserve muscle force after fasting. Force/frequency curve of FGF21f/f (left panel) and FGF21−/− (right panel).”
Gene-expression group list repeats control-starved mice and omits knockout-starved mice
MinorThe methods list four experimental conditions but name the control-starved group twice. The results report gene-expression measurements in knockout muscles during fasting, a group absent from that list.
“At least four samples of each experimental condition (FGF21f/f FED, FGF21f/f STARVED, FGF21−/− FED, and FGF21f/f STARVED) were analysed.”
“The expression levels of the well‐known muscle‐specific E3 ubiquitin ligases Atrogin1 and MuRF1, as well as the recently discovered SMART, MUSA1, Fbxo31, Itch, and Trim37,37 were the same in control and knockout muscles in both fed and fasting state”
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FoxO3 Controls Autophagy in Skeletal Muscle In Vivo
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Self-citationSUnSET, a nonradioactive method to monitor protein synthesis
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Autophagy is required to maintain muscle mass.
Masiero, E., Agatea, L., Mammucari, C., Blaauw, B., Loro, E., Komatsu, M., Metzger, D., Reggiani, C., Schiaffino, S., & Sandri, M. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.10.008 · Cited by 1,282 · see citing works
Self-citationMuscle wasting in disease: molecular mechanisms and promising therapies
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Understanding the Physiology of FGF21
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Thermogenic Activation Induces FGF21 Expression and Release in Brown Adipose Tissue
Hondares, E., Iglesias, R., Giralt, A., Gonzalez, F. J., Giralt, M., Mampel, T., & Villarroya, F. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.215889 · Cited by 623 · see citing works
Mitochondrial fission and remodelling contributes to muscle atrophy
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Self-citationCirculating FGF21 Is Liver Derived and Enhances Glucose Uptake During Refeeding and Overfeeding
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“In agreement, a positive correlation of serum FGF21 levels and aging-sarcopenia has been found.(18,21) Importantly, FGF21 deletion in OPA1 knockout”
BackgroundInfluentialSelf-citationSearching for the exercise factor: is IL-6 a candidate?
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Mitochondrial quality control and muscle mass maintenance.
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FGF21 is an Akt‐regulated myokine
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Mechanisms of muscle atrophy and hypertrophy: implications in health and disease
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The Interplay between Mitochondrial Morphology and Myomitokines in Aging Sarcopenia
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Association between serum FGF21 level and sarcopenia in older adults
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Myokines: Metabolic regulation in obesity and type 2 diabetes
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- Authors
- Oost, L. J., Kustermann, M., Armani, A., Blaauw, B., & Romanello, V.
- Affiliations
- Veneto Institute of Molecular Medicine (IT)
- Universität Ulm (DE)
- University of Padua (IT)
- Corresponding author
- Romanello, Vanina
- Venue
- Journal of Cachexia, Sarcopenia and Muscle
- Publisher
- Wiley
- Published
- 2019-03-20
- Volume
- 10
- Issue
- 3
- Pages
- 630-642
- ISSN
- 2190-5991 (ISSN-L)
- 2190-6009
- PMC
- PMC6596457
- OpenAlex
- W2923886615
- Semantic Scholar
- b67918291bb786d2ab13425760071f6aff9ed205
- Cited by
- 231
- References
- 44
- Citations by year
- 2026: 22 · 2025: 36 · 2024: 34 · 2023: 44 · 2022: 24 · 2021: 40 · 2020: 23 · 2019: 8
- FWCI
- 7.86
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Cachexia Sarcopenia and Muscle (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Radboud Repository (Radboud University) (submittedVersion)
- Padua Research Archive (University of Padova) (submittedVersion)
- Radboud Repository (Radboud University) (submittedVersion, other-oa)
- Funders
- American Federation for Medical Research (21865)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Health Sciences › Medicine › Physiology › Adipose Tissue and Metabolism
- Keywords
- FGF21, mitophagy, skeletal muscle mass, muscle atrophy, fasting, BNIP3, muscle weakness, muscle protein synthesis, autophagy, myokines, muscle-specific knockout mice, sarcopenia, cancer cachexia, diabetes mellitus, muscle homeostasis, endoplasmic reticulum stress, mitochondrial dysfunction, muscle fiber type
- MeSH terms
- Animals, Disease Models, Animal, Fasting, Fibroblast Growth Factors, Humans, Membrane Proteins, Mitochondria, Muscular Atrophy, Mice, Knockout, Muscle, Skeletal, Mitochondrial Proteins, Mice, 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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