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Cited by 940Muscle Physiology and DisordersMuscle metabolism and nutritionNutrition and Health in Aging

Mechanisms of muscle atrophy and hypertrophy: implications in health and disease

Open access
Sartori, Roberta, Romanello, Vanina, Sandri, Marco·2021·Nature Communications
DOI 10.1038/s41467-020-20123-1PMC PMC7803748
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Abstract

Skeletal muscle is the protein reservoir of our body and an important regulator of glucose and lipid homeostasis. Consequently, the growth or the loss of muscle mass can influence general metabolism, locomotion, eating and respiration. Therefore, it is not surprising that excessive muscle loss is a bad prognostic index of a variety of diseases ranging from cancer, organ failure, infections and unhealthy ageing. Muscle function is influenced by different quality systems that regulate the function of contractile proteins and organelles. These systems are controlled by transcriptional dependent programs that adapt muscle cells to environmental and nutritional clues. Mechanical, oxidative, nutritional and energy stresses, as well as growth factors or cytokines modulate signaling pathways that, ultimately, converge on protein and organelle turnover. Novel insights that control and orchestrate such complex network are continuously emerging and will be summarized in this review. Understanding the mechanisms that control muscle mass will provide therapeutic targets for the treatment of muscle loss in inherited and non-hereditary diseases and for the improvement of the quality of life during ageing.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes molecular mechanisms controlling skeletal muscle atrophy and hypertrophy, emphasizing the balance between protein/organelle synthesis and degradation. It highlights signaling pathways, degradation systems, nonautologous signals, and therapeutic targets, while noting that no effective pharmacological treatment for muscle loss is yet in the clinic.

Key findings

  • Skeletal muscle is 40–50% of total body mass in healthy-weight individuals and acts as the body’s protein reservoir; excessive muscle loss is a poor prognostic index in cancer, organ failure, infections, and unhealthy ageing.
  • Hypertrophy and atrophy are not simply increased synthesis/decreased degradation versus the reverse: exercise activates both protein synthesis and autophagy–lysosome/ubiquitin–proteasome degradation, and amino acids released during breakdown can stimulate mTOR.
  • Major growth pathways include Insulin/IGF1-AKT-mTOR, TGFβ/myostatin/activin/BMP, and β-adrenergic signaling; major atrophy pathways include FoxO-atrogenes, TNFα-IKK-IκB-NF-κB, IL6-JAK-Stat3, ATF4/ER stress, and mitochondrial dysfunction.
  • The ubiquitin–proteasome and autophagy–lysosome systems are central to atrophy; MuRF1 knockout mice are not protected from denervation-induced muscle loss at 7 days and only partially protected (around 30%) at 14 days, while Atrogin-1 inhibition does not block denervation- or glucocorticoid-induced loss.

Methods

  • Design: narrative review summarizing molecular mechanisms of muscle atrophy and hypertrophy and their implications in health and disease.
  • Data/sample: no primary experimental sample; the paper synthesizes findings from cited animal models, cell studies, human trials, and prior literature.
  • Main analysis: qualitative synthesis of signaling pathways, degradation systems, nonautologous signals, and therapeutic approaches; no systematic search, meta-analysis, or quantitative pooling is described.

Limitations

  • The paper states that successful pharmacological treatments for atrophying muscle are absent in the clinic and that “our view of the mechanistic insights that control atrophying muscle is still limited and needs further exploration.”
  • Evident from the text: as a narrative review, it does not report a systematic search strategy, inclusion/exclusion criteria, risk-of-bias assessment, or meta-analysis.
  • Evident from the text: several pathways are described as “novel and emerging” or needing consolidation, with dotted lines in figures indicating mechanisms not completely defined in adult skeletal muscle.

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

Integrity signals

Registry

Crossref · 10.1038/s41467-020-20123-1

Cites

100 of 100 references verified0 citation errors · 0 not checkable

Statistics

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Claims the paper makes

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  • Premisecitation

    Slow muscles such as the soleus are less sensitive to starvation compared to fast muscles.

    “For instance, slow muscles, such as the soleus, are less sensitive to starvation compared to fast muscles2, while during disuse such as that induced by hind limb suspension, the soleus atrophies faster than glycolytic (fast) muscles3.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [2] Sandri, M. et al. PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc. Natl Acad. Sci. USA 103, 16260–16265 (2006). source

      Not checked in the free run.

  • Premisecitation

    Among IGF1 isoforms, IGF-1Ea is the most powerful in increasing muscle mass and force both in young and aged mice.

    “Among the different IGF1 isoforms, which differ in the N‐terminal signal peptide (Class 1 or 2) and the C‐terminal extension peptide (E‐peptide Ea or Eb), IGF-1Ea is the most powerful in increasing muscle mass and force both in young and aged mice7.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Ascenzi, F. et al. Effects of IGF-1 isoforms on muscle growth and sarcopenia. Aging Cell 18, e12954 (2019). source

      Not checked in the free run.

  • Premisenone given

    Insulin and IGF1 are potent anabolic factors that sustain organism and muscle growth.

    “Insulin and insulin-like growth factor 1 (IGF1) are potent anabolic factors that sustain organism and muscle growth.”
    Quote in the paperSubstantial claim
  • Premisecitation

    During disuse such as that induced by hind limb suspension, the soleus atrophies faster than glycolytic (fast) muscles.

    “For instance, slow muscles, such as the soleus, are less sensitive to starvation compared to fast muscles2, while during disuse such as that induced by hind limb suspension, the soleus atrophies faster than glycolytic (fast) muscles3.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [3] Brocca, L. et al. FoxO-dependent atrogenes vary among catabolic conditions and play a key role in muscle atrophy induced by hindlimb suspension. J. Physiol. 595, 1143–1158 (2017). source

      Not checked in the free run.

  • Premisecitation

    mTOR integrates multiple stimuli and signals to the translation machinery via p70S6K1 and 4EBP1.

    “This kinase integrates multiple stimuli coming not only from hormones but also from cytokines, nutrients, ATP/AMP ratio, and signals to the translation machinery via p70S6K1, which controls the ribosomal protein S6, and factor 4E binding protein 1 (4EBP1), which negatively regulates the ribosomal eukaryotic translation initiator factor 4E5.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [5] Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020). source

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  • Classified as probably not a substantial claim. 5
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  • Classified as probably not a substantial claim.

    Premisereasoning

    During exercise or anabolic hormonal stimulation, muscles grow because new proteins and organelles accumulate in the cytosol, increasing cellular volume, a process named hypertrophy.

    “In fact, during exercise or anabolic hormonal stimulation, muscles grow because new proteins and organelles accumulate in the cytosol increasing cellular volume, a process named hypertrophy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Exercise promotes the synthesis of new proteins but simultaneously activates autophagy-lysosome and ubiquitin-proteasome degradative systems.

    “In fact, exercise does promote the synthesis of new proteins but simultaneously activates autophagy–lysosome and ubiquitin–proteasome-degradative systems4.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [4] Grumati, P. et al. Physical exercise stimulates autophagy in normal skeletal muscles but is detrimental for collagen VI-deficient muscles. Autophagy 7, 1415–1423 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Skeletal muscle is the protein reservoir of the body and is fundamental for glucose, amino acid, and lipid homeostasis.

    “Being the most abundant tissue (40–50% of the total mass in healthy-weight individual) and the protein reservoir in the human body, skeletal muscles not only control locomotion but they are fundamental for breathing, eating, energy expenditure, as well as for glucose, amino acids, and lipids homeostasis and for maintaining a high quality of life1.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [1] Baskin, K. K., Winders, B. R. & Olson, E. N. Muscle as a “mediator” of systemic metabolism. Cell Metab. 21, 237–248 (2015). source

      Not checked in the free run.

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

    Premisenone given

    mTOR forms two complexes: the rapamycin-sensitive TORC1 complex containing Raptor and the rapamycin-insensitive TORC2 complex containing Rictor.

    “The mTOR kinase interacts with several proteins to form two different complexes, the rapamycin-sensitive TORC1 complex, which contains Raptor, and the rapamycin-insensitive TORC2 complex, which contains Rictor (Fig. 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Each catabolic condition differs in muscle susceptibility to atrophy and induction of an atrophy program, and within the same catabolic situation different muscles activate peculiar atrophy-related programs.

    “Therefore, each catabolic condition differs from the others in terms of muscle susceptibility to atrophy as well as induction of an atrophy program and within the same catabolic situation, different muscles activate peculiar atrophy-related programs3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [3] Brocca, L. et al. FoxO-dependent atrogenes vary among catabolic conditions and play a key role in muscle atrophy induced by hindlimb suspension. J. Physiol. 595, 1143–1158 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Skeletal muscles are heterogeneous with respect to fiber type and metabolic properties and vary, often drastically, in their response to the same stimulus.

    “First, skeletal muscles are heterogeneous with respect to fiber type and metabolic properties and therefore they vary, often drastically, in their response to the same stimulus.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [2] Sandri, M. et al. PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc. Natl Acad. Sci. USA 103, 16260–16265 (2006). source

      Not checked in the free run.

    • cites [3] Brocca, L. et al. FoxO-dependent atrogenes vary among catabolic conditions and play a key role in muscle atrophy induced by hindlimb suspension. J. Physiol. 595, 1143–1158 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    mTORC2 is related to glucose and lipid homeostasis, while mTORC1 regulates anabolic processes including protein synthesis, ribosome, and mitochondria biogenesis.

    “While mTORC2 is related to glucose and lipids homeostasis5, mTORC1 regulates several anabolic processes, including protein synthesis, ribosome, and mitochondria biogenesis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020). source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisereasoning

    Catabolic conditions such as cancer, infections, diabetes, organ failure, or inactivity/disuse promote a net loss of proteins, organelles, and cytoplasm, causing shrinkage of cellular volume, a condition named atrophy.

    “Conversely, catabolic conditions such as cancer, infections, diabetes, organ failure, or inactivity/disuse promote a net loss of proteins, organelles, and cytoplasm causing shrinkage of the cellular volume, a condition named atrophy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Constitutively active AKT results in striking hypertrophy of transfected muscle fibers, with a similar effect using inducible muscle-specific transgenic models.

    “Accordingly, constitutively active AKT results in striking hypertrophy of transfected muscle fibers9, with a similar effect being seen using inducible muscle-specific transgenic models10.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [9] Pallafacchina, G., Calabria, E., Serrano, A. L., Kalhovde, J. M. & Schiaffino, S. A protein kinase B-dependent and rapamycin-sensitive pathway controls skeletal muscle growth but not fiber type specification. Proc. Natl Acad. Sci. USA 99, 9213–9218 (2002). source

      Not checked in the free run.

    • cites [10] Blaauw, B. et al. Inducible activation of Akt increases skeletal muscle mass and force without satellite cell activation. Faseb J. 23, 3896–3905 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    During protein breakdown, amino acids released by lysosome and proteasome directly stimulate mTOR, so protein synthesis might increase during muscle atrophy.

    “Conversely, during protein breakdown, the amino acids released by lysosome and proteasome directly stimulate mTOR5 and therefore, protein synthesis might increase during muscle atrophy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Liu, G. Y. & Sabatini, D. M. mTOR at the nexus of nutrition, growth, ageing and disease. Nat. Rev. Mol. Cell Biol. 21, 183–203 (2020). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle-specific Rictor knockout mice do not show any overt phenotype, whereas Raptor- and mTOR-deficient mice display reduced postnatal growth due to reduced size of fast but not slow muscle fibers and a progressive muscular dystrophy phenotype.

    “While muscle-specific Rictor knockout mice do not show any overt phenotype conversely, Raptor- and mTOR-deficient mice display reduced postnatal growth, due to the reduced size of fast but not slow muscle fibers and a progressive muscular dystrophy phenotype11,12.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [11] Bentzinger, C. F. et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 8, 411–424 (2008). source

      Not checked in the free run.

    • cites [12] Risson, V. et al. Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy. J. Cell Biol. 187, 859–874 (2009). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    mTORC1 has a major role in muscle homeostasis but may not be the exclusive regulator of protein synthesis, and autophagy in muscles is controlled by mTORC1 independent and dependent pathways.

    “Altogether these findings suggest that mTORC1 has a major role in muscle homeostasis but may not be the exclusive regulator of protein synthesis and that autophagy in muscles is controlled by mTORC1 independent and dependent pathways.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    BMP signaling converges on Smad4 and controls muscle mass.

    “Another pathway that converges on Smad4 and controls muscle mass is BMP signaling19,20.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [19] Sartori, R. et al. BMP signaling controls muscle mass. Nat. Genet. 45, 1309–1318 (2013). source

      Not checked in the free run.

    • cites [20] Traore, M. et al. An embryonic CaVbeta1 isoform promotes muscle mass maintenance via GDF5 signaling in adult mouse. Sci. Transl. Med. 11, eaaw1131 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    β2-adrenergic signaling at least partially impinges on insulin/IGF1 receptor signaling and not on the ERK1 pathway.

    “Recent data suggest that β2-adrenergic signaling, at least partially, impinges on insulin/IGF1 receptor signaling and not on the ERK1 pathway25.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Goncalves, D. A. et al. Insulin/IGF1 signalling mediates the effects of beta2 -adrenergic agonist on muscle proteostasis and growth. J. Cachexia Sarcopenia Muscle 10, 455–475 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of plakoglobin enhances PI3K-AKT-FoxO signaling and promotes muscle growth.

    “Overexpression of plakoglobin enhances PI3K–AKT-FoxO signaling and promotes muscle growth28.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [28] Cohen, S., Lee, D., Zhai, B., Gygi, S. P. & Goldberg, A. L. Trim32 reduces PI3K-Akt-FoxO signaling in muscle atrophy by promoting plakoglobin-PI3K dissociation. J. Cell Biol. 204, 747–758 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Specific ablation of Smad4 in the skeletal muscle of mice did not promote hypertrophy but caused atrophy and weakness.

    “Interestingly, specific ablation of Smad4 in the skeletal muscle of mice did not promote hypertrophy but caused atrophy and weakness19.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Sartori, R. et al. BMP signaling controls muscle mass. Nat. Genet. 45, 1309–1318 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Increase of ZIP14 promotes muscle loss, and muscle-specific deletion of ZIP14 prevents muscle loss in tumor-bearing mice.

    “Conversely, the increase of the metal-ion transporter ZRT- and IRT-like protein 14 (ZIP14), which controls the uptake of Zn ions, has been shown to promote muscle loss. ZIP14 is upregulated by TNF-α and TGF-β cytokines and ZIP14-dependent zinc accumulation induces myosin heavy chain loss, while muscle-specific deletion of ZIP14 prevents muscle loss in tumor-bearing mice30.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Wang, G. et al. Metastatic cancers promote cachexia through ZIP14 upregulation in skeletal muscle. Nat. Med. 24, 770–781 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PGC1α transgenic mice do not show muscle growth and do not display enhancement of protein synthesis, but the splicing isoform PGC1α4 promotes muscle hypertrophy.

    “However, despite the fact that PGC1α transgenic mice do not show muscle growth and do not display an enhancement of protein synthesis, the splicing isoform 4 (PGC1α4) was found to promote muscle hypertrophy32.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Ruas, J. L. et al. A PGC-1alpha isoform induced by resistance training regulates skeletal muscle hypertrophy. Cell 151, 1319–1331 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Follistatin-mediated hypertrophy not only blocks myostatin signaling but simultaneously stimulates Smad1/5/8 activation.

    “Consistently, follistatin-mediated hypertrophy not only blocks myostatin signaling but simultaneously stimulates Smad1/5/8 activation19,22,23.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] Sartori, R. et al. BMP signaling controls muscle mass. Nat. Genet. 45, 1309–1318 (2013). source

      Not checked in the free run.

    • cites [22] Davey, J. R. et al. Integrated expression analysis of muscle hypertrophy identifies Asb2 as a negative regulator of muscle mass. JCI Insight 1, e85477 (2016). source

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    • cites [23] Winbanks, C. E. et al. The bone morphogenetic protein axis is a positive regulator of skeletal muscle mass. J. Cell Biol. 203, 345–357 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of Atrogin-1 does not block denervation- and glucocorticoid-induced muscle loss and does not protect from aging sarcopenia.

    “Inhibition of Atrogin-1 does not block denervation- and glucocorticoids-induced muscle loss19,44 and does not protect from aging sarcopenia46.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] Sartori, R. et al. BMP signaling controls muscle mass. Nat. Genet. 45, 1309–1318 (2013). source

      Not checked in the free run.

    • cites [44] Baehr, L. M., Furlow, J. D. & Bodine, S. C. Muscle sparing in muscle RING finger 1 null mice: response to synthetic glucocorticoids. J. Physiol. 589, 4759–4776 (2011). source

      Not checked in the free run.

    • cites [46] Sandri, M. et al. Signalling pathways regulating muscle mass in ageing skeletal muscle. The role of the IGF1-Akt-mTOR-FoxO pathway. Biogerontology 14, 303–323 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Alteration in lipid composition due to downregulation of Perilipin2 is sufficient to induce hypertrophy and prevent muscle atrophy after denervation, and this hypertrophy seems largely mTOR-independent because rapamycin did not prevent muscle growth after Perilipin2 knockdown.

    “For instance, alteration in lipid composition due to the downregulation of the lipid-associated protein Perilipin2 is sufficient to induce hypertrophy and prevent muscle atrophy after denervation38. Interestingly, this type of hypertrophy seems to be largely mTOR-independent because rapamycin treatment did not prevent muscle growth after Perilipin2 knockdown.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [38] Conte, M. et al. Muscle-specific Perilipin2 down-regulation affects lipid metabolism and induces myofiber hypertrophy. J. Cachexia Sarcopenia Muscle 10, 95–110 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing). May combine two claims.

    Premisecitation

    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.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Oost, L. J., Kustermann, M., Armani, A., Blaauw, B. & Romanello, V. Fibroblast growth factor 21 controls mitophagy and muscle mass. J. Cachexia Sarcopenia Muscle 10, 630–642 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Conditional deletion of mTOR with concomitant expression of catalytically inactive mTOR resulted in a growth rate defect starting after 1 week of age, and these mice show more severe muscle loss than conditional RAPTOR knockout.

    “Conditional deletion of mTOR with a concomitant expression of catalytically inactive mTOR, resulted in a growth rate defect that started after 1 week of age. Importantly, these mice show a more severe muscle loss when compared with the conditional RAPTOR knockout11.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Bentzinger, C. F. et al. Skeletal muscle-specific ablation of raptor, but not of rictor, causes metabolic changes and results in muscle dystrophy. Cell Metab. 8, 411–424 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Atrogin-1/MAFbx and MuRF1 are the first ubiquitin ligases identified to play a role in muscle loss, are strongly upregulated in all catabolic conditions so far tested in animals, and are considered the master genes of muscle atrophy.

    “The first ubiquitin ligases that were identified to play a role in muscle loss were Atrogin-1/MAFbx and MuRF1. These two E3s are strongly upregulated in all the catabolic conditions so far tested in animals and are considered the master genes of muscle atrophy39.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [39] Bodine, S. C. et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294, 1704–1708 (2001). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MuRF1 knockout mice are not protected from denervation-induced muscle loss at 7 days and only partially protected (around 30%) at 14 days; absence of MuRF1 does not protect from fasting or microgravity-induced atrophy, while muscle mass is spared following glucocorticoid treatment.

    “MuRF1 knockout mice are not protected from denervation-induced muscle loss at 7 days and only partially protected (around 30%) at 14 days39. Moreover, the absence of MuRF1 does not protect from fasting or microgravity induced atrophy, while muscle mass is spared following glucocorticoid treatment43,44.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [39] Bodine, S. C. et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 294, 1704–1708 (2001). source

      Not checked in the free run.

    • cites [43] Cadena, S. M. et al. Skeletal muscle in MuRF1 null mice is not spared in low-gravity conditions, indicating atrophy proceeds by unique mechanisms in space. Sci. Rep. 9, 9397 (2019). source

      Not checked in the free run.

    • cites [44] Baehr, L. M., Furlow, J. D. & Bodine, S. C. Muscle sparing in muscle RING finger 1 null mice: response to synthetic glucocorticoids. J. Physiol. 589, 4759–4776 (2011). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The anabolic action of IGF1 requires the activity of ATP citrate lyase, which is phosphorylated and activated by AKT, resulting in improved mitochondrial respiration and ATP production.

    “For instance, the anabolic action of IGF1 requires the activity of ATP citrate lyase (ACL), a cytosolic enzyme that catalyzes the conversion of mitochondrial-derived citrate into oxaloacetate and acetyl-CoA. Indeed, ACL is phosphorylated and activated by AKT resulting in an improvement of mitochondrial respiration and ATP production34.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [34] Das, S. et al. ATP citrate lyase improves mitochondrial function in skeletal muscle. Cell Metab. 21, 868–876 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Myostatin is a member of the TGFβ superfamily and is the most well-known member in the muscle field because of the profound hypermuscularity of Myostatin knockout mice.

    “Myostatin is the most well-known member of this superfamily, in the muscle field, because of the profound hypermuscularity of Myostatin knockout mice16.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] McPherron, A. C., Lawler, A. M. & Lee, S. J. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature 387, 83–90 (1997). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Trim32 controls the thin filaments (actin, tropomyosin, troponins), the Z-band protein α-actinin, and desmin.

    “Trim32 has been found to control the thin filaments (actin, tropomyosin, troponins), the Z-band protein α-actinin, and desmin47.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Cohen, S., Zhai, B., Gygi, S. P. & Goldberg, A. L. Ubiquitylation by Trim32 causes coupled loss of desmin, Z-bands, and thin filaments in muscle atrophy. J. Cell Biol. 198, 575–589 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The gut microbiota generates metabolites including glycine, alanine, and choline that can positively regulate muscle mass, and germ-free mice show increased plasma glucocorticoids, decreased IGF1 and PGC1α expression, altered mitochondrial function, and induction of catabolic enzymes for BCAAs leading to poor quality muscles.

    “The gut microbiota generates several metabolites including amino acids like glycine and alanine and the neurotransmitter precursor choline that can positively regulate muscle mass. Indeed, germ-free mice show an increased plasma level of glucocorticoids, decreased IGF1 and PGC1α expression, alteration of mitochondrial function, and induction of catabolic enzymes for branched-chain amino acids (BCA”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Lahiri, S. et al. The gut microbiota influences skeletal muscle mass and function in mice. Sci. Transl. Med. 11, eaan5662 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Both conditional mTOR knockout and mTOR catalytically inactive transgenic mice show myofiber degeneration and a myopathic phenotype, suggesting an important pro-survival role of mTOR.

    “However, both conditional mTOR knockout and mTOR catalytical inactive transgenic mice show myofiber degeneration and myopathic phenotype, suggesting an important pro-survival role of mTOR.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Risson, V. et al. Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy. J. Cell Biol. 187, 859–874 (2009). source

      Not checked in the free run.

    • cites [14] Zhang, Q. et al. Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis. J. Cachexia Sarcopenia Muscle 10, 35–53 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UBR4 is critical for hypertrophy and induces hypertrophy via ubiquitination and degradation of a core set of target proteins, including the HAT1/RBBP4/RBBP7 histone-binding complex, that control histone acetylation and expression of growth-promoting genes.

    “However, a recent RNAi screening for the ubiquitin ligases that control muscle mass identified UBR4 as a critical one for hypertrophy37. UBR4 induces hypertrophy via ubiquitination and degradation of a core set of target proteins, including the HAT1/RBBP4/RBBP7 histone-binding complex, that control histone acetylation and expression of growth-promoting genes.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [37] Hunt, L. C. et al. A key role for the ubiquitin ligase UBR4 in myofiber hypertrophy in Drosophila and mice. Cell Rep. 28, 1268–1281 e1266 (2019). source

      Not checked in the free run.

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    Premisecitation

    Inhibition of Smad2/3 is sufficient to promote muscle growth, suggesting that genes involved in protein turnover are targets of these transcription factors.

    “Importantly, just inhibition of Smad2/3 is sufficient to promote muscle growth17,18, suggesting that genes involved in protein turnover are the target of these transcription factors.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Sartori, R. et al. Smad2 and 3 transcription factors control muscle mass in adulthood. Am. J. Physiol. Cell Physiol. 296, C1248–C1257 (2009). source

      Not checked in the free run.

    • cites [18] Winbanks, C. E. et al. Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin. J. Cell Biol. 197, 997–1008 (2012). source

      Not checked in the free run.

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    Premisecitation

    Inducible muscle-specific deletion of Raptor blocks muscle hypertrophy but does not blunt the increase of protein synthesis in a mechanical overload model.

    “For instance, inducible muscle-specific deletion of Raptor does block muscle hypertrophy but does not blunt the increase of protein synthesis, revealed by puromycin incorporation, in a mechanical overload model13.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [13] You, J. S. et al. The role of raptor in the mechanical load-induced regulation of mTOR signaling, protein synthesis, and skeletal muscle hypertrophy. FASEB J. 33, 4021–4034 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A slow and progressive myopathic phenotype was described in mice with chronic mTORC1 activation by TSC1 inhibition, and the autophagy system was blocked and contributed to the phenotype.

    “A slow and progressive myopathic phenotype was also described in mice that displayed a chronic mTORC1 activation by TSC1 inhibition15. Consistent with mTOR hyperactivation, the autophagy system was blocked and this impairment contributed to the phenotype of TSC1 knockout15.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Castets, P. et al. Sustained activation of mTORC1 in skeletal muscle inhibits constitutive and starvation-induced autophagy and causes a severe, late-onset myopathy. Cell Metab. 17, 731–744 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autophagy is not hyperactivated in conditional mTOR knockout and mTOR catalytically inactive mice, but instead is impaired, and this inhibition contributes to the pathological features of these animals.

    “Surprisingly, autophagy is not hyperactivated in these mice, as might be expected to occur following inhibition of the mTORC1 complex (Fig. 1), but instead is impaired and this inhibition greatly contributes to the pathological features of these animals12,14.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [12] Risson, V. et al. Muscle inactivation of mTOR causes metabolic and dystrophin defects leading to severe myopathy. J. Cell Biol. 187, 859–874 (2009). source

      Not checked in the free run.

    • cites [14] Zhang, Q. et al. Lack of muscle mTOR kinase activity causes early onset myopathy and compromises whole-body homeostasis. J. Cachexia Sarcopenia Muscle 10, 35–53 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rapamycin treatment or mTOR knockdown reverts the hypertrophic effect of myostatin blockade, indicating cross-talk between myostatin and the AKT/mTOR axis.

    “Indeed, rapamycin treatment or mTOR knockdown revert the hypertrophic effect of myostatin blockade17,18.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [17] Sartori, R. et al. Smad2 and 3 transcription factors control muscle mass in adulthood. Am. J. Physiol. Cell Physiol. 296, C1248–C1257 (2009). source

      Not checked in the free run.

    • cites [18] Winbanks, C. E. et al. Follistatin-mediated skeletal muscle hypertrophy is regulated by Smad3 and mTOR independently of myostatin. J. Cell Biol. 197, 997–1008 (2012). source

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  • May combine two claims.

    Interpretationcitation

    Overexpression of the BMP antagonist noggin reverted the hypertrophic phenotype of myostatin knockout mice, arguing for genetic epistasis between the activin/myostatin and BMP pathways in muscle.

    “The finding that overexpression of the BMP antagonist noggin reverted the hypertrophic phenotype of myostatin knockout mice, strongly argues in favor of genetic epistasis between the activin/myostatin and BMP pathways in muscle.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [19] Sartori, R. et al. BMP signaling controls muscle mass. Nat. Genet. 45, 1309–1318 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The Activin/Myostatin/TGFβ group binds ActRIIB/IIA and TGFβRII and, through ALK-4, -7, and -5, induces phosphorylation of Smad2/3 to form a heterotrimeric complex with Smad4.

    “The Activin/Myostatin/TGFβ group binds plasma membrane-associated activin type IIB and type IIA receptors (ActRIIB/IIA) and TGFβ receptors (TGFβRII) and, through the recruitment and activation of activin receptor-like kinase (ALK)-4, -7, and -5, induce phosphorylation of Smad2/3 to promote the formation of a heterotrimeric complex with Smad4 (Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    MuRF1 inhibition prevents age-related muscle loss but not the decrease in muscle force.

    “Finally, MuRF1 inhibition prevents age-related muscle loss but not the decrease in muscle force45,46.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [45] Hwee, D. T., Baehr, L. M., Philp, A., Baar, K. & Bodine, S. C. Maintenance of muscle mass and load-induced growth in muscle RING Finger 1 null mice with age. Aging Cell 13, 92–101 (2014). source

      Not checked in the free run.

    • cites [46] Sandri, M. et al. Signalling pathways regulating muscle mass in ageing skeletal muscle. The role of the IGF1-Akt-mTOR-FoxO pathway. Biogerontology 14, 303–323 (2013). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Lys48-linked polyubiquitin chains signal proteasome-dependent degradation, while Lys63-linked polyubiquitin chains regulate autophagy-dependent cargo recognition by interacting with p62.

    “Lys48-linked polyubiquitin chains are a signal for proteasome-dependent degradation, while Lys63-linked polyubiquitin chains play other roles, such as regulating autophagy-dependent cargo recognition by interacting with the scaffold protein p62 (also known as SQSTM1)40.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Pankiv, S. et al. p62/SQSTM1 binds directly to Atg8/LC3 to facilitate degradation of ubiquitinated protein aggregates by autophagy. J. Biol. Chem. 282, 24131–24145 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle hypertrophy induced by β2-adrenergic agonists such as clenbuterol or formoterol is accompanied by a significant increase in AKT phosphorylation and is completely blocked by rapamycin.

    “Muscle hypertrophy induced by β2-adrenergic agonists, such as clenbuterol or formoterol, is accompanied by a significant increase in AKT phosphorylation and is completely blocked by rapamycin24.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Kline, W. O., Panaro, F. J., Yang, H. & Bodine, S. C. Rapamycin inhibits the growth and muscle-sparing effects of clenbuterol. J. Appl. Physiol. 102, 740–747 (2007). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Administration of FGF19 promoted muscle hypertrophy and increased grip strength without AKT activation but with ERK stimulation.

    “It has been recently reported that administration of FGF19 promoted muscle hypertrophy and increased grip strength without AKT activation but with ERK stimulation26.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Benoit, B. et al. Fibroblast growth factor 19 regulates skeletal muscle mass and ameliorates muscle wasting in mice. Nat. Med. 23, 990–996 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DKK3 downregulation reduces age-related muscle loss but not cancer- or fasting-mediated muscle atrophy.

    “DKK3 is upregulated in aging and its overexpression caused muscle atrophy, while its downregulation reduced age-related muscle loss but not cancer- or fasting-mediated muscle atrophy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Yin, J. et al. Dkk3 dependent transcriptional regulation controls age related skeletal muscle atrophy. Nat. Commun. 9, 1752 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When nutrients are available, mTORC1 promotes nuclear relocalization of Foxk, which binds to promoters of autophagy genes, recruits Sin3A-HDAC complex, and compacts chromatin, preventing FoxO3 recruitment.

    “When nutrients are available, the mTORC1 complex promotes nuclear relocalization of Foxk, which binds to the promoters of autophagy genes, recruits the Sin3A-HDAC complex, and compacts chromatin, therefore preventing FoxO3 recruitment.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [81] Bowman, C. J., Ayer, D. E. & Dynlacht, B. D. Foxk proteins repress the initiation of starvation-induced atrophy and autophagy programs. Nat. Cell Biol. 16, 1202–1214 (2014). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FoxO1,3,4 are transcription factors downstream of the IGF1/insulin-Akt pathway, and their inhibition completely spares muscle loss and force drop in fasting, hind limb suspension, immobilization, diabetes, and glucocorticoids treatment.

    “FoxO1,3,4 are transcription factors downstream the IGF1/insulin-Akt pathway (Fig. 1) and their inhibition completely spares muscle loss and force drop in fasting, hind limb suspension, immobilization, diabetes, and glucocorticoids treatment3,57,63,64.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [3] Brocca, L. et al. FoxO-dependent atrogenes vary among catabolic conditions and play a key role in muscle atrophy induced by hindlimb suspension. J. Physiol. 595, 1143–1158 (2017). source

      Not checked in the free run.

    • cites [57] Milan, G. et al. Regulation of autophagy and the ubiquitin-proteasome system by the FoxO transcriptional network during muscle atrophy. Nat. Commun. 6, 6670 (2015). source

      Not checked in the free run.

    • cites [63] O’Neill, B. T. et al. FoxO transcription factors are critical regulators of diabetes-related muscle atrophy. Diabetes 68, 556–570 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Reactivation of autophagy in aged mice by expressing Atg7 in skeletal muscle or treating with Urolithin A ameliorates muscle mass.

    “Reactivation of autophagy in aged mice both by expressing Atg7 in skeletal or by treating mice with Urolithin A, a compound that promotes mitophagy, ameliorate muscle mass51,56.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [51] Carnio, S. et al. Autophagy impairment in muscle induces neuromuscular junction degeneration and precocious aging. Cell Rep. 8, 1509–1521 (2014). source

      Not checked in the free run.

    • cites [56] Ryu, D. et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 22, 879–888 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mettl21e negatively regulates 26S proteasome activity, while Mettl21c is crucial for autophagy regulation.

    “While Mettl21e negatively regulates 26S proteasome activity, Mettl21c seems to be crucial for autophagy regulation.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [61] Wang, C. et al. Methyltransferase-like 21c methylates and stabilizes the heat shock protein Hspa8 in type I myofibers in mice. J. Biol. Chem. 294, 13718–13728 (2019). source

      Not checked in the free run.

    • cites [62] Wiederstein, J. L. et al. Skeletal muscle-specific methyltransferase METTL21C trimethylates p97 and regulates autophagy-associated protein breakdown. Cell Rep. 23, 1342–1356 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Muscle-specific overexpression of IKKβ in transgenic mice leads to severe muscle wasting mediated, at least in part, by the ubiquitin ligase MuRF1, but not by atrogin-1/MAFbx.

    “Muscle-specific overexpression of IKKβ in transgenic mice leads to severe muscle wasting mediated, at least in part, by the ubiquitin ligase MuRF1, but not by atrogin-1/MAFbx71.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [71] Cai, D. et al. IKKbeta/NF-kappaB activation causes severe muscle wasting in mice. Cell 119, 285–298 (2004). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Gadd45α induces remodeling of chromatin to repress genes involved in anabolic signaling and energy production and to activate pro-atrophy genes including autophagy and caspase-related genes.

    “Gadd45α induces the remodeling of chromatin to repress genes involved in anabolic signaling and energy production and to activate pro-atrophy genes including autophagy and caspase-related genes74.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Ebert, S. M. et al. Stress-induced skeletal muscle Gadd45a expression reprograms myonuclei and causes muscle atrophy. J. Biol. Chem. 287, 27290–27301 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of Stat3 is sufficient to induce muscle atrophy and to upregulate atrogin-1.

    “Moreover, overexpression of Stat3 is sufficient to induce muscle atrophy and to upregulate atrogin-173.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Bonetto, A. et al. JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia. Am. J. Physiol. Endocrinol. Metab. 303, E410–E421 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Acute inhibition of OPA1 induces oxidative stress, systemic inflammatory response, muscle atrophy, premature tissue senescence, that altogether cause animal death.

    “Acute inhibition of OPA1 induces oxidative stress, systemic inflammatory response, muscle atrophy, premature tissue senescence, that altogether cause animal death77.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Tezze, C. et al. Age-associated loss of OPA1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence. Cell Metab. 25, 1374–1389 e1376 (2017). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fn14 is upregulated in denervated muscle, allowing NF-κB activation and consequently MuRF1 but not atrogin-1/MAFbx expression.

    “Fn14 is upregulated in denervated muscle allowing NF-κB activation and consequently MuRF1 but not atrogin-1/MAFbx expression72.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Mittal, A. et al. The TWEAK-Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice. J. Cell Biol. 188, 833–849 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    p300/CBP-mediated acetylation inhibits the FoxO3-dependent atrophy program, while HDAC-mediated deacetylation activates FoxOs.

    “For instance, p300/CBP-mediated acetylation inhibits FoxO3-dependent atrophy program, while HDAC-mediated deacetylation activates FoxOs65,66.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [65] Beharry, A. W. et al. HDAC1 activates FoxO and is both sufficient and required for skeletal muscle atrophy. J. Cell Sci. 127, 1441–1453 (2014). source

      Not checked in the free run.

    • cites [66] Bertaggia, E., Coletto, L. & Sandri, M. Posttranslational modifications control FoxO3 activity during denervation. Am. J. Physiol. Cell Physiol. 302, C587–C596 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The p97/VCP ATPase complex extracts and degrades ubiquitinated proteins from larger structures including myofibrils, is induced during denervation, and overexpression of a dominant-negative p97/VCP reduces overall proteolysis by the proteasome and lysosome pathways.

    “Finally, another player is the p97/valosin-containing protein (VCP) ATPase complex whose function is to extract and degrade ubiquitinated proteins from larger structures, including myofibrils60. p97/VCP is induced during denervation, and overexpression of a dominant-negative p97/VCP reduces overall proteolysis by the proteasome and lysosome pathways.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Piccirillo, R. & Goldberg, A. L. The p97/VCP ATPase is critical in muscle atrophy and the accelerated degradation of muscle proteins. EMBO J. 31, 3334–3350 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DRP1 ablation alters calcium homeostasis and mitochondria-ER tethering resulting in myofiber degeneration but with normal animal survival.

    “Conversely, DRP1 ablation alters calcium homeostasis and mitochondria–ER tethering resulting in myofiber degeneration but with normal animal survival78.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Favaro, G. et al. DRP1-mediated mitochondrial shape controls calcium homeostasis and muscle mass. Nat. Commun. 10, 2576 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Asb2b is a muscle-specific ubiquitin ligase repressed by Follistatin and critical for hypertrophy; its inhibition is permissive for growth, while its overexpression causes muscle atrophy.

    “An exception is the muscle-specific ubiquitin ligase, SOCS box protein 2 (Asb2b)22, which was identified to be repressed by Follistatin and to be critical for hypertrophy. In fact, while its inhibition is permissive for growth, its overexpression causes muscle atrophy22.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Davey, J. R. et al. Integrated expression analysis of muscle hypertrophy identifies Asb2 as a negative regulator of muscle mass. JCI Insight 1, e85477 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    JunB, PGC1α, and PGC1β inhibit FoxO activity in skeletal muscles, while the glucocorticoid receptor and β-catenin synergize with FoxOs to promote muscle wasting.

    “For instance, JunB, PGC1α, and PGC1β all inhibit FoxO activity in skeletal muscles2,67,68, while the glucocorticoid receptor and β−catenin synergize with FoxOs to promote muscle wasting69.”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [2] Sandri, M. et al. PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc. Natl Acad. Sci. USA 103, 16260–16265 (2006). source

      Not checked in the free run.

    • cites [67] Brault, J. J., Jespersen, J. G. & Goldberg, A. L. Peroxisome proliferator-activated receptor gamma coactivator 1alpha or 1beta overexpression inhibits muscle protein degradation, induction of ubiquitin ligases, and disuse atrophy. J. Biol. Chem. 285, 19460–19471 (2010). source

      Not checked in the free run.

    • cites [68] Raffaello, A. et al. JunB transcription factor maintains skeletal muscle mass and promotes hypertrophy. J. Cell Biol. 191, 101–113 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    The ULK1-2/Fip200/Atg13/Atg101 complex is an upstream activator of autophagy and is blocked by mTORC1 and induced by AMPK.

    “In the cell, the ULK1-2/Fip200/Atg13/Atg101 complex is an upstream activator of the autophagy system (Fig. 3) and is modulated by nutrients and energy-sensitive pathways, such as mTOR and AMPK. The ULK1 complex is blocked by mTORC1 and is induced by AMPK.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Cancer and sepsis induce Stat3 phosphorylation in muscles.

    “Interestingly, cancer and sepsis induce Stat3 phosphorylation in muscles and Stat3 inhibition spares muscle mass in tumor-bearing mice73 (Fig. 5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Bonetto, A. et al. JAK/STAT3 pathway inhibition blocks skeletal muscle wasting downstream of IL-6 and in experimental cancer cachexia. Am. J. Physiol. Endocrinol. Metab. 303, E410–E421 (2012). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TWEAK knockout mice display reduced NF-κB activation and MuRF1 expression.

    “TWEAK knockout mice display less atrophy during denervation as well as reduced NF-κB activation and MuRF1 expression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [72] Mittal, A. et al. The TWEAK-Fn14 system is a critical regulator of denervation-induced skeletal muscle atrophy in mice. J. Cell Biol. 188, 833–849 (2010). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Absence of CK2 prevents import of PINK1 inside mitochondrial intermembrane space via TOM22 resulting in PINK1 accumulation, which triggers Parkin recruitment and mitophagy.

    “while the absence of casein kinase 2 (CK2) prevents the import of PINK1 inside the mitochondrial intermembrane space via TOM22 resulting in PINK1 accumulation, which triggers Parkin recruitment and mitophagy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Kravic, B. et al. In mammalian skeletal muscle, phosphorylation of TOMM22 by protein kinase CSNK2/CK2 controls mitophagy. Autophagy 14, 311–335 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A specific inhibitor of MuRF1 was developed and a protective effect in atrophying muscles of mice with heart failure was found.

    “Interestingly, a specific inhibitor of the muscle-specific ubiquitin ligase MuRF1 was developed and a protective effect in atrophying muscles of mice with heart failure was found100.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [100] Adams, V. et al. Small-molecule-mediated chemical knock-down of MuRF1/MuRF2 and attenuation of diaphragm dysfunction in chronic heart failure. J. Cachexia Sarcopenia Muscle 10, 1102–1115 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Autophagy flux is impaired in CK2 knockout leading to formation of p62-positive protein aggregates and myopathy.

    “However, autophagy flux is impaired in CK2 knockout leading to the formation of p62-positive protein aggregates and myopathy83.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [83] Kravic, B. et al. In mammalian skeletal muscle, phosphorylation of TOMM22 by protein kinase CSNK2/CK2 controls mitophagy. Autophagy 14, 311–335 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Clenbuterol or formoterol enhance protein synthesis and inhibit protein degradation.

    “Clenbuterol or formoterol are β2-adrenoreceptor agonists that in addition to stimulating the breakdown of glycogen and lipids, enhance protein synthesis and inhibit protein degradation25.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Goncalves, D. A. et al. Insulin/IGF1 signalling mediates the effects of beta2 -adrenergic agonist on muscle proteostasis and growth. J. Cachexia Sarcopenia Muscle 10, 455–475 (2019). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Spermidine prevents acetylation of autophagy proteins by blocking EP300 acetyltransferase, maintains autophagy flux, preserves mitochondrial function, exhibits anti-inflammatory properties, and prevents stem cell senescence.

    “Acetylation of autophagy proteins plays an inhibitory action, and the polyamine spermidine, by blocking the EP300 acetyltransferase, prevents this post-translational modification, maintains autophagy flux, preserves mitochondrial function, exhibits anti-inflammatory properties, and prevents stem cell senescence98.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Pietrocola, F. et al. Spermidine induces autophagy by inhibiting the acetyltransferase EP300. Cell Death Differ. 22, 509–516 (2015). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ghrelin induces GH-IGF1 axis and reduces atrophy.

    “Among these, ghrelin is a hormone secreted from the stomach, which, by acting on the hypothalamus and the pituitary gland, induces GH-IGF1 axis and reduces atrophy95.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Porporato, P. E. et al. Acylated and unacylated ghrelin impair skeletal muscle atrophy in mice. J. Clin. Investig. 123, 611–622 (2013).

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of TGFβ signaling in muscle stem cells upregulates Twist-1, which enhances myostatin expression.

    “Consistently, the activation of TGFβ signaling in muscle stem cells upregulates the Twist-1 transcription factor, which enhances myostatin expression.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Parajuli, P. et al. Twist1 activation in muscle progenitor cells causes muscle loss akin to cancer cachexia. Dev. Cell 45, 712–725 e716 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Treatment with Tat-Beclin1 in inducible muscle-specific Raptor knockout mice restored a normal mitochondrial membrane potential and reduced myofiber denervation.

    “Treatment with Tat-Beclin1 in inducible muscle-specific Raptor knockout mice, which showed autophagy impairment and several features of sarcopenia such as mitochondrial dysfunction, atrophy, and denervation, restored a normal mitochondrial membrane potential and reduced myofiber denervation97.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [97] Baraldo, M. et al. Skeletal muscle mTORC1 regulates neuromuscular junction stability. J. Cachexia Sarcopenia Muscle 11, 208–225 (2019). source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationreasoning

    The lack of any efficient drug that counteracts muscle loss suggests that our view of the mechanistic insights that control atrophying muscle is still limited and needs further exploration.

    “The lack of any efficient drug that counteracts muscle loss suggests that our view of the mechanistic insights that control atrophying muscle is still limited and needs further exploration.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: No efficient pharmacological treatment for atrophying muscle is available in the clinic.

  • May combine two claims.

    Premisecitation

    Treatment with nicotinamide mononucleotide improves mitochondrial respiration and prevents aging-associated gene expression changes in muscles of mice and humans.

    “Recently, treatment with nicotinamide mononucleotide, which enhances NAD + production, has been shown to improve mitochondrial respiration and to prevent aging-associated gene expression changes in muscles of mice and humans92.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [92] Mills, K. F. et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 24, 795–806 (2016). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FAPs in denervated muscles activate an inflammatory response program and become the most abundant source of IL6.

    “The FAPs in denervated muscles activate an inflammatory response program and become the most abundant source of IL6.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [87] Madaro, L. et al. Denervation-activated STAT3-IL-6 signalling in fibro-adipogenic progenitors promotes myofibres atrophy and fibrosis. Nat. Cell Biol. 20, 917–927 (2018). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Regular exercise extends life expectancy and reduces morbidity in aging.

    “longitudinal studies have shown that regular exercise extends life expectancy and reduces morbidity in aging89,90.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [89] Ekelund, U. et al. Does physical activity attenuate, or even eliminate, the detrimental association of sitting time with mortality? A harmonised meta-analysis of data from more than 1 million men and women. Lancet 388, 1302–1310 (2016). source

      Not checked in the free run.

    • cites [90] Chakravarty, E. F., Hubert, H. B., Lingala, V. B. & Fries, J. F. Reduced disability and mortality among aging runners: a 21-year longitudinal study. Arch. Intern. Med. 168, 1638–1646 (2008). source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Urolithin A selectively activates mitophagy in muscle and improves muscle function in aging.

    “Recently, urolithin A, a metabolite of ellagitannins that are abundant in pomegranate fruit, as well as in nuts and berries was shown to selectively activate mitophagy in muscle and improve muscle function in aging.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Ryu, D. et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 22, 879–888 (2016). source

      Not checked in the free run.

73 of 73

  • The authors state this as an assumption.

    Metabolic adaptations occurring in skeletal muscles work as a disease modifier.

    “Consistently, the metabolic adaptations occurring in skeletal muscles are assumed to work as a disease modifier and the quality of muscle mass is an important predictor of mortality1.”

  • The paper relies on this without support.

    Understanding the mechanisms that control muscle mass will provide therapeutic targets for treating muscle loss in inherited and non-hereditary diseases and for improving quality of life during ageing.

    “Understanding the mechanisms that control muscle mass will provide therapeutic targets for the treatment of muscle loss in inherited and non-hereditary diseases and for the improvement of the quality of life during ageing.”

  • The paper relies on this without support.

    No efficient pharmacological treatment for atrophying muscle is available in the clinic.

    “successful pharmacological treatments for atrophying muscle are absent in the clinic”
3 of 3

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?

  • GLP-1RA-induced reductions in protein intake, lower insulin/IGF-1 and negative energy balance converge to suppress mTOR signaling, reducing muscle protein synthesis.

    “GLP-1RA-induced reductions in protein intake, lower insulin/IGF-1 and negative energy balance converge to suppress mTOR signaling, reducing muscle protein synthesis [31].”

    From Muscle loss and GLP-1R agonists use (2025) · cites this paper as [31]

  • Decreased insulin and IGF-1 signaling lowers mTOR activity, shifting the balance toward muscle catabolism.

    “Decreased insulin and IGF-1 signaling lowers mTOR activity, shifting the balance toward muscle catabolism [31].”

    From Muscle loss and GLP-1R agonists use (2025) · cites this paper as [31]

  • Reduced mechanical loading decreases the stimulus for muscle protein synthesis, exacerbating lean tissue loss.

    “Reduced mechanical loading decreases the stimulus for muscle protein synthesis, exacerbating lean tissue loss [31].”

    From Muscle loss and GLP-1R agonists use (2025) · cites this paper as [31]

  • Skeletal muscle is an important mediator of insulin action and glucose homeostasis and contributes substantially to energy expenditure.

    “Skeletal muscle is an important mediator of insulin action and glucose homeostasis and contributes substantially to energy expenditure (EE) [10].”

    From Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism (2024) · cites this paper as [10]

  • Changes in muscle mass are mediated by rates of protein synthesis and degradation which result in muscle growth or atrophy, respectively.

    “Notably, changes in muscle mass are mediated by rates of protein synthesis and degradation which result in muscle growth or atrophy, respectively [10].”

    From Antibody blockade of activin type II receptors preserves skeletal muscle mass and enhances fat loss during GLP-1 receptor agonism (2024) · cites this paper as [10]

Cites

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Authors
Sartori, R., Romanello, V., & Sandri, M.
Affiliations
University of Padua (IT)
Corresponding author
  • Romanello, Vanina
  • Sandri, Marco
ORCID
Venue
Nature Communications
Publisher
Springer Science and Business Media LLC
Published
2021-01-12
Volume
12
Issue
1
Pages
330-330
ISSN
2041-1723 (ISSN-L)
DOI
10.1038/s41467-020-20123-1
PMC
PMC7803748
OpenAlex
W3121032204
Semantic Scholar
6b031d2898572d17bbe596979ea5c5b6ad71b860
Cited by
940
References
100
Citations by year
2026: 180 · 2025: 222 · 2024: 195 · 2023: 163 · 2022: 131 · 2021: 48
FWCI
14.21
Type
journal article
Language
en
Open access
Licence
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, other-oa)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Padua Research Archive (University of Padova) (submittedVersion, cc-by)
Funders
AFM-Téléthon (22457)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
  • Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
Keywords
muscle atrophy, muscle hypertrophy, skeletal muscle, muscle mass regulation, protein turnover, organelle turnover, transcriptional regulation, mechanical stress, oxidative stress, nutrient signaling, energy stress, growth factors, cytokines, aging, cancer cachexia, therapeutic target
MeSH terms
Animals, Disease, Health, Humans, Hypertrophy, Muscular Atrophy, Signal Transduction, Muscle Development

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.

Statistics and arithmetic are recomputed, not judged.

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