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Cited by 153Muscle Physiology and DisordersNutrition and Health in AgingMitochondrial Function and Pathology

Mitochondria initiate and regulate sarcopenia

Open access
Alway, Stephen E., Mohamed, Junaith S., Myers, Matthew J.·2017·Exercise and Sport Sciences Reviews
DOI 10.1249/jes.0000000000000101PMC PMC5357179
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Abstract

We present the hypothesis that an accumulation of dysfunctional mitochondria initiates a signaling cascade leading to motor neuron and muscle fiber death and culminating in sarcopenia. Interactions between neural and muscle cells that contain dysfunctional mitochondria exacerbate sarcopenia. Preventing sarcopenia will require identifying mitochondrial sources of dysfunction that are reversible.

AI snapshot

Written from the paper’s full text.

TL;DR

This review proposes that age-related accumulation of dysfunctional mitochondria in muscle cells and motor neurons initiates apoptotic signaling and cell death, leading to sarcopenia, with neural–muscle cross talk exacerbating the process. It argues that preventing sarcopenia requires identifying reversible mitochondrial sources of dysfunction, especially through mitophagy, exercise, and nutrition.

Key findings

  • The central hypothesis is that mitochondrial deterioration in muscles and motor neurons is the primary initiator of sarcopenia; increased mPTP opening releases mitochondrial contents to the cytosol, initiating apoptosis and nuclear DNA fragmentation, leading to fiber and motor neuron death.
  • Sarcopenia in aged humans and rodents is associated with motor neuronal death, impaired innervation, and a ~27% reduction in the motor unit pool; loss of innervation induces profound muscle atrophy.
  • Proposed mitochondrial sources of damage include ROS, mtDNA deletions/mutations, and denervation; aging also attenuates mitophagy, allowing dysfunctional mitochondria to persist, with Mfn2 decline implicated as a possible bridge, though conflicting data exist.
  • Exercise and nutritional interventions are proposed to improve mitochondrial health by increasing mitophagy and mitochondrial biogenesis, but the paper notes uncertainty about whether new mitochondria in aged hosts are healthy and whether antioxidants should be used when elderly begin exercise.

Methods

  • Design: conceptual/hypothesis review; no primary experimental study is reported.
  • Data or sample: Not stated in the paper; the paper cites published studies in aged humans, rodents, and cell/mouse models rather than presenting its own sample.
  • Main analysis: narrative synthesis and development of hypothetical models (Figures 1 and 2); no formal statistical or systematic analysis is reported.

Limitations

  • The paper states the hypothesis is based on speculation and requires additional work; it specifically notes lack of data for aging-associated localized motor neuron disassembly outside neural degenerative disease.
  • The paper acknowledges conflicting evidence, including whether Mfn2 declines or mitophagy is reduced in aged muscle, and inconsistent UPS/atrogene findings across studies.
  • Evident from the text: as a narrative review, it provides no primary data, systematic search, or causal test of the mitochondrial-initiation hypothesis.

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

Integrity signals

Registry

Crossref · 10.1249/jes.0000000000000101

Cites

150 of 150 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 170 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Loss of CuZnSOD in either neural or muscle cells recapitulates sarcopenic muscle loss in a mouse model.

    “both neural and muscle losses of the cytosolic antioxidant CuZn-superoxide dismutase (CuZnSOD) recapitulated sarcopenic muscle loss in a mouse model (125).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Sataranatarajan K Qaisar R Davis C Sakellariou GK Vasilaki A Zhang Y Liu Y Bhaskaran S McArdle A Jackson M Brooks SV Richardson A Van RH Neuron specific reduction in CuZnSOD is not sufficient to initiate a full sarcopenia phenotype Redox. Biol 2015 5 140 148 25917273 PMC5022075 source

      Not checked in the free run.

  • Interpretationcitation

    Accumulation of excessive ROS contributes to damaged and dysfunctional mitochondria in muscle and neural cells.

    “it is clear that accumulation of excessive ROS contributes to damaged and dysfunctional mitochondria in muscle and neural cells.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [15] Brand MD Mitochondrial generation of superoxide and hydrogen peroxide as the source of mitochondrial redox signaling Free Radic. Biol. Med 2016 27085844 source

      Not checked in the free run.

    • cites [125] Sataranatarajan K Qaisar R Davis C Sakellariou GK Vasilaki A Zhang Y Liu Y Bhaskaran S McArdle A Jackson M Brooks SV Richardson A Van RH Neuron specific reduction in CuZnSOD is not sufficient to initiate a full sarcopenia phenotype Redox. Biol 2015 5 140 148 25917273 PMC5022075 source

      Not checked in the free run.

  • Premisecitation

    Loss of mitochondrial function with aging is shared by muscle cells and motor neurons.

    “It is interesting that a loss of mitochondria function with aging is a mechanism that is shared by both muscle cells (18, 63) and motor neurons (123).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [18] Calvani R Joseph AM Adhihetty PJ Miccheli A Bossola M Leeuwenburgh C Bernabei R Marzetti E Mitochondrial pathways in sarcopenia of aging and disuse muscle atrophy Biol. Chem 2013 394 393 414 23154422 PMC3976204 source

      Not checked in the free run.

    • cites [63] Joseph AM Adhihetty PJ Wawrzyniak NR Wohlgemuth SE Picca A Kujoth GC Prolla TA Leeuwenburgh C Dysregulation of mitochondrial quality control processes contribute to sarcopenia in a mouse model of premature aging PLoS. One 2013 8 e69327 23935986 PMC3720551 source

      Not checked in the free run.

    • cites [123] Rygiel KA Grady JP Turnbull DM Respiratory chain deficiency in aged spinal motor neurons Neurobiol. Aging 2014 35 2230 2238 24684792 PMC4099519 source

      Not checked in the free run.

  • Premisecitation

    Absence of CuZnSOD in either neural or muscle cells alone does not produce full sarcopenic muscle loss.

    “the absence of CuZnSOD in either neural or muscle cells did not manifest full sarcopenic muscle loss (125).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] Sataranatarajan K Qaisar R Davis C Sakellariou GK Vasilaki A Zhang Y Liu Y Bhaskaran S McArdle A Jackson M Brooks SV Richardson A Van RH Neuron specific reduction in CuZnSOD is not sufficient to initiate a full sarcopenia phenotype Redox. Biol 2015 5 140 148 25917273 PMC5022075 source

      Not checked in the free run.

  • Premisecitation

    In aging, loss of innervation induces profound muscle atrophy.

    “In aging, a loss of innervation induces profound muscle atrophy (5, 106, 129).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [5] Alway SE Degens H Krishnamurthy G Chaudhrai A Denervation stimulates apoptosis but not Id2 expression in hindlimb muscles of aged rats J Gerontol. A Biol. Sci Med Sci 2003 58 687 697 12902526 source

      Not checked in the free run.

    • cites [106] Pannerec A Springer M Migliavacca E Ireland A Piasecki M Karaz S Jacot G Metairon S Danenberg E Raymond F Descombes P McPhee JS Feige JN A robust neuromuscular system protects rat and human skeletal muscle from sarcopenia Aging (Albany. NY) 2016 8 712 729 27019136 PMC4925824

      Not checked in the free run.

    • cites [129] Siu PM Alway SE Mitochondria-associated apoptotic signalling in denervated rat skeletal muscle J. Physiol 2005 565 309 323 15774533 PMC1464486 source

      Not checked in the free run.

  • Classified as probably not a substantial claim. 12
  • May combine two claims. 38

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

    Interpretationreasoning

    Cross talk between muscles and motor neurons containing dysfunctional mitochondria exacerbates sarcopenia.

    “Cross talk between muscles and motor neurons that contain dysfunctional mitochondria exacerbates sarcopenia.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Loss of mitophagy-proteasome-induced mitochondrial clearance in muscle and motor neuron cells promotes accumulation of poorly functioning mitochondria with increased mPTP opening.

    “A loss of mitophagy-proteasome-induced mitochondrial clearance in muscle and motor neuron cells promotes accumulation of poorly functioning mitochondria that have increased mPTP opening.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Aging suppression of autophagy activators such as SIRT1 and Mfn2 prevents removal of dysfunctional mitochondria via mitophagy and proteasome digestion.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationreasoning

    Removal of nuclei in muscle cells and motor neurons leads to fiber and motor neuron death and loss of innervation to muscle cells.

    “Removal of nuclei in muscle cells and motor neurons leads to fiber and motor neuron death and loss of innervation to the muscle cells.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Leaked mitochondrial contents initiate intrinsic apoptotic signaling leading to DNA fragmentation and nuclear apoptosis in a localized fiber region.

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

    Interpretationnone given

    Aging increases mitochondrial stress that sensitizes opening of the mitochondrial permeability transition pore.

    “Aging increases mitochondrial stress that sensitizes the opening of the mitochondria transition permeability pore (mPTP).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Sarcopenia in aged humans and rodents is associated with motor neuronal death, impaired innervation, and about a 27% reduction in the motor unit pool.

    “sarcopenia in aged humans and rodents is also associated with motor neuronal death (96, 139), which causes impaired innervation (48, 106), and a ~27% reduction in the motor unit pool.”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [96] Mittal KR Logmani FH Age-related reduction in 8th cervical ventral nerve root myelinated fiber diameters and numbers in man J Gerontol 1987 42 8 10 3794203

      Not checked in the free run.

    • cites [139] Tomlinson BE Irving D The numbers of limb motor neurons in the human lumbosacral cord throughout life J Neurol. Sci 1977 34 213 219 925710

      Not checked in the free run.

    • cites [48] Hepple RT Rice CL Innervation and neuromuscular control in ageing skeletal muscle J Physiol 2016 594 1965 1978 26437581 PMC4933121

      Not checked in the free run.

    • cites [106] Pannerec A Springer M Migliavacca E Ireland A Piasecki M Karaz S Jacot G Metairon S Danenberg E Raymond F Descombes P McPhee JS Feige JN A robust neuromuscular system protects rat and human skeletal muscle from sarcopenia Aging (Albany. NY) 2016 8 712 729 27019136 PMC4925824

      Not checked in the free run.

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

    Interpretationreasoning

    Mitochondrial deterioration in muscle cells and motor neurons is the primary initiator of sarcopenia.

    “Our current perspective and hypothesis is that mitochondrial deterioration in muscles and motor neurons is the primary initiator of sarcopenia (Figure 1).”
    • Also stated in: § Mitochondrial regulation of sarcopenia - Hypothesis · plain
      “Thus, mitochondria are key initiators and regulators of sarcopenia (Figure 1).”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: Local mitochondrial damage causes increased mPTP opening.
    • The authors state this as an assumption: mPTP opening triggers mitochondrial contents to leak into the cytosol.
    • The authors state this as an assumption: Leaked mitochondrial contents initiate intrinsic apoptotic signaling leading to DNA fragmentation and nuclear apoptosis in a localized fiber region.
    • Rests on an assumption: Aging suppression of autophagy activators such as SIRT1 and Mfn2 prevents removal of dysfunctional mitochondria via mitophagy and proteasome digestion.

  • May combine two claims.

    Premisecitation

    Aging increases ROS production and lowers antioxidant enzyme levels in muscle and neuron cells.

    “Aging increases ROS production (22), and lowers antioxidant enzymes levels in muscle and neuron cells (58, 59, 121).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [22] Carter HN Chen CC Hood DA Mitochondria, muscle health, and exercise with advancing age Physiology. (Bethesda.) 2015 30 208 223 25933821

      Not checked in the free run.

    • cites [58] Jackson JR Ryan MJ Alway SE Long-term supplementation with resveratrol alleviates oxidative stress but does not attenuate sarcopenia in aged mice J Gerontol. A Biol. Sci Med. Sci 2011 66 751 764 21454355 PMC3143346

      Not checked in the free run.

    • cites [59] Jackson JR Ryan MJ Hao Y Alway SE Mediation of endogenous antioxidant enzymes and apoptotic signaling by resveratrol following muscle disuse in the gastrocnemius muscles of young and old rats Am. J Physiol Regul. Integr. Comp Physiol 2010 299 R1572 R1581 20861279 PMC3007185

      Not checked in the free run.

    • cites [121] Ryan MJ Jackson JR Hao Y Leonard SS Alway SE Inhibition of xanthine oxidase reduces oxidative stress and improves skeletal muscle function in response to electrically stimulated isometric contractions in aged mice Free Radic. Biol. Med 2011 51 38 52 21530649 PMC3430730

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    mtDNA deletions or mutations contribute to mitochondrial dysfunction and aging-related muscle fiber loss and atrophy.

    “Mitochondrial DNA (mtDNA) deletions or DNA mutations contribute to mitochondrial dysfunction and aging-related muscle fiber loss and atrophy (50, 90).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] Herbst A Wanagat J Cheema N Widjaja K McKenzie D Aiken JM Latent mitochondrial DNA deletion mutations drive muscle fiber loss at old age Aging Cell 2016 PMC5114866 27561813

      Not checked in the free run.

    • cites [90] McKenzie D Bua E McKiernan S Cao Z Aiken JM Mitochondrial DNA deletion mutations: a causal role in sarcopenia Eur. J Biochem 2002 269 2010 2015 11985577

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S1 (asserted), S4 (based). May combine two claims.

    Interpretationreasoning

    Leakage of mitochondrial contents into the cytosol initiates apoptosis signaling in muscle cells and motor neurons, contributing to nuclear DNA fragmentation and apoptosis.

    “Leakage of the mitochondrial contents to the cell cytosol initiates death (apoptosis) signaling in muscle cells and motor neurons, which contributes to nuclear DNA fragmentation and if not repaired, nuclear apoptosis.”
    Quote in the paperNot a substantial claim
    • The authors state this as an assumption: mPTP opening triggers mitochondrial contents to leak into the cytosol.
    • The authors state this as an assumption: Leaked mitochondrial contents initiate intrinsic apoptotic signaling leading to DNA fragmentation and nuclear apoptosis in a localized fiber region.

  • May combine two claims.

    Premisecitation

    Sarcopenia is associated with increased apoptosis and reduced muscle regeneration, leading to muscle wasting.

    “Sarcopenia, is associated with increased levels of apoptosis (47) and reduced capabilities for muscle regeneration (41) leading to muscle wasting.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [47] Hao Y Jackson JR Wang Y Edens N Pereira SL Alway SE ß-Hydroxy-ß-methylbutyrate reduces myonuclear apoptosis during recovery from hind limb suspension-induced muscle fiber atrophy in aged rats Am. J. Physiol Regul. Integr. Comp Physiol 2011 301 R701 R715 21697520 PMC3174754

      Not checked in the free run.

    • cites [41] Garcia-Prat L Sousa-Victor P Munoz-Canoves P Functional dysregulation of stem cells during aging: a focus on skeletal muscle stem cells FEBS J 2013 280 4051 4062 23452120 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Some denervated fibers become reinnervated by axons from surviving motor neurons, while others remain denervated and contribute to functional losses in sarcopenia.

    “Some denervated fibers become innervated by axons from surviving motor neurons (42, 45), whereas other fibers remain denervated and contribute to functional losses in sarcopenia (42).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [42] Gilmore KJ Morat T Doherty TJ Rice CL Motor Unit Number Estimations and Neuromuscular Fidelity in Three Stages of Sarcopenia Muscle Nerve 2016 27576772

      Not checked in the free run.

    • cites [45] Gutmann E Hanzlikova V Denervation, reinnervation and regeneration of senile muscle Adv. Exp. Med Biol 1975 53 431 440 123404

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Opening the mPTP releases mitochondrial contents into the cytosol and initiates apoptotic signaling.

    “Opening the mPTP induces a further loss of mitochondrial membrane potential, and releases the mitochondrial contents to the cytosol to initiate apoptotic signaling (24, 77, 89).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [24] Chabi B Ljubicic V Menzies KJ Huang JH Saleem A Hood DA Mitochondrial function and apoptotic susceptibility in aging skeletal muscle Aging. Cell 2008 7 2 12 18028258 source

      Not checked in the free run.

    • cites [77] Leeuwenburgh C Gurley CM Strotman BA Dupont-Versteegden EE Age-related differences in apoptosis with disuse atrophy in soleus muscle Am. J Physiol Regul. Integr. Comp Physiol 2005 288 R1288 R1296 15650125

      Not checked in the free run.

    • cites [89] Marzetti E Wohlgemuth SE Lees HA Chung HY Giovannini S Leeuwenburgh C Age-related activation of mitochondrial caspase-independent apoptotic signaling in rat gastrocnemius muscle Mech. Ageing. Dev 2008 129 542 549 18579179 PMC2585824 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockout of Mfn1/2 in skeletal muscle prevented mitochondrial fusion, increased mtDNA defects, and resulted in muscle atrophy.

    “a knockout of Mfn 1/2 in skeletal muscle, which prevented mitochondrial fusion, increased the accumulation of mtDNA defects and resulted in muscle atrophy (31).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Correia-Melo C Marques FD Anderson R Hewitt G Hewitt R Cole J Carroll BM Miwa S Birch J Merz A Rushton MD Charles M Jurk D Tait SW Czapiewski R Greaves L Nelson G Bohlooly Y Rodriguez-Cuenca S Vidal-Puig A Mann D Saretzki G Quarato G Green DR Adams PD von ZT Korolchuk VI Passos JF Mitochondria are required for pro-ageing features of the senescent phenotype EMBO J 2016 35 724 742 26848154 PMC4818766 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mfn2 declines in muscle with aging, and loss of Mfn2 produces an aging-like phenotype including mitochondrial dysfunction, higher ROS, and muscle fiber atrophy.

    “Recent data by Sebastián and colleagues (127) show that Mfn2 declines in muscle with aging and loss of Mfn2 produces an aging-like phenotype, including age-associated mitochondrial dysfunction, higher ROS accumulation and muscle fiber atrophy.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [127] Sebastian D Sorianello E Segales J Irazoki A Ruiz-Bonilla V Sala D Planet E Berenguer-Llergo A Munoz JP Sanchez-Feutrie M Plana N Hernandez-Alvarez MI Serrano AL Palacin M Zorzano A Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway EMBO J 2016 35 1677 1693 27334614 PMC4969577 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Other studies found higher fusion profiles in muscles of humans and prematurely aged mice, and larger mitochondria in muscles of old mice.

    “other studies have found higher fusion profiles in muscles of humans (14), and prematurely aged mice (63), and larger mitochondria in muscles of old mice (75).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [14] Bori Z Zhao Z Koltai E Fatouros IG Jamurtas AZ Douroudos II Terzis G Chatzinikolaou A Sovatzidis A Draganidis D Boldogh I Radak Z The effects of aging, physical training, and a single bout of exercise on mitochondrial protein expression in human skeletal muscle Exp. Gerontol 2012 47 417 424 22449457 PMC4915826

      Not checked in the free run.

    • cites [63] Joseph AM Adhihetty PJ Wawrzyniak NR Wohlgemuth SE Picca A Kujoth GC Prolla TA Leeuwenburgh C Dysregulation of mitochondrial quality control processes contribute to sarcopenia in a mouse model of premature aging PLoS. One 2013 8 e69327 23935986 PMC3720551 source

      Not checked in the free run.

    • cites [75] Leduc-Gaudet JP Picard M Jean PF St Sgarioto N Auger MJ Vallee J Robitaille R Pierre DH St Gouspillou G Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice Oncotarget 2015 6 17923 17937 26053100 PMC4627226 source

      Not checked in the free run.

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

    Premisecitation

    Aging-induced mtDNA deletions are associated with loss of mitochondrial function in motor neurons, neuronal malfunction in Parkinson's disease, and muscle loss with aging.

    “aging-induced mtDNA deletions are closely associated with a loss of mitochondrial function in motor neurons (123), neuronal malfunction in diseases like Parkinson’s disease (115), and muscle loss with aging (50, 91).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [123] Rygiel KA Grady JP Turnbull DM Respiratory chain deficiency in aged spinal motor neurons Neurobiol. Aging 2014 35 2230 2238 24684792 PMC4099519

      Not checked in the free run.

    • cites [115] Reeve A Meagher M Lax N Simcox E Hepplewhite P Jaros E Turnbull D The impact of pathogenic mitochondrial DNA mutations on substantia nigra neurons J Neurosci 2013 33 10790 10801 23804100 PMC6618501

      Not checked in the free run.

    • cites [50] Herbst A Wanagat J Cheema N Widjaja K McKenzie D Aiken JM Latent mitochondrial DNA deletion mutations drive muscle fiber loss at old age Aging Cell 2016 PMC5114866 27561813

      Not checked in the free run.

    • cites [91] McKiernan SH Colman R Lopez M Beasley TM Weindruch R Aiken JM Longitudinal analysis of early stage sarcopenia in aging rhesus monkeys Exp. Gerontol 2009 44 170 176 18983905 PMC2693938

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In neurons, DNA damage precedes apoptosis, and forced repair of DNA damage rescues neurons from apoptosis.

    “In neurons, DNA damage precedes neuronal apoptosis (85), whereas forced repair of DNA damage rescues neurons from elimination by apoptosis (86).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [85] Martin LJ Liu Z Injury-induced spinal motor neuron apoptosis is preceded by DNA single-strand breaks and is p53- and Bax-dependent J Neurobiol 2002 50 181 197 11810634

      Not checked in the free run.

    • cites [86] Martin LJ Wong M Enforced DNA repair enzymes rescue neurons from apoptosis induced by target deprivation and axotomy in mouse models of neurodegeneration Mech. Ageing Dev 2016 PMC5192008 27364693

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  • May combine two claims.

    Premisecitation

    Muscles of aged rodents and humans have a greater overall rate of fission versus fusion and lower Opa1 levels than younger muscles.

    “muscles of aged rodents and humans have a greater overall rate of fission vs. fusion (55, 62) and lower levels of the fusion protein Opa1 (62) as compared with younger muscles.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [55] Ibebunjo C Chick JM Kendall T Eash JK Li C Zhang Y Vickers C Wu Z Clarke BA Shi J Cruz J Fournier B Brachat S Gutzwiller S Ma Q Markovits J Broome M Steinkrauss M Skuba E Galarneau JR Gygi SP Glass DJ Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia Mol. Cell Biol 2013 33 194 212 23109432 PMC3554128

      Not checked in the free run.

    • cites [62] Joseph AM Adhihetty PJ Buford TW Wohlgemuth SE Lees HA Nguyen LM Aranda JM Sandesara BD Pahor M Manini TM Marzetti E Leeuwenburgh C The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals Aging Cell 2012 11 801 809 22681576 PMC3444680 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fiber atrophy and apoptotic signaling did not occur in regions of the same muscle fibers located further from dysfunctional mitochondria.

    “fiber atrophy and apoptotic signaling did not occur in other regions of the same muscle fibers that were located further away from the dysfunctional mitochondrial (26).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Cheema N Herbst A McKenzie D Aiken JM Apoptosis and necrosis mediate skeletal muscle fiber loss in age-induced mitochondrial enzymatic abnormalities Aging Cell 2015 14 1085 1093 26365892 PMC4693455

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    If degenerative processes were systemic rather than local, uniform muscle fiber wasting across length would be expected, but this is not observed.

    “If the degenerative processes were not initiated locally but rather from a more general or systemic source, we would expect uniform muscle fiber wasting across its length, but this is not the case.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Cheema et al. observed localized aging-induced loss of mitochondrial enzymes SDH and COX, with the same fiber region being atrophic and having high caspase-3.

    “Cheema et al. (26) observed a localized aging-induced loss of the mitochondrial enzymes succinate dehydrogenase and cytochrome c oxidase. Interestingly, the same fiber region that had mitochondrial disruption was both atrophic and had high levels of the apoptotic protein caspase-3.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Cheema N Herbst A McKenzie D Aiken JM Apoptosis and necrosis mediate skeletal muscle fiber loss in age-induced mitochondrial enzymatic abnormalities Aging Cell 2015 14 1085 1093 26365892 PMC4693455

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Acceleration of protein turnover with net protein loss is downstream of dysfunctional mitochondria and is a major contributor to sarcopenia.

    “An acceleration of protein turnover with a net loss of protein is downstream of dysfunctional mitochondria but this represents a major contributor to sarcopenia.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    FOXOs control MTORC1 signaling, which is associated with muscle hypertrophy and inhibition of mitophagy in skeletal muscle.

    “FOXOs control the mammalian target of rapamycin complex 1 (MTORC1) signaling, which is associated with muscle hypertrophy (43) and inhibition of mitophagy in skeletal muscle (23).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [43] Goodman CA Frey JW Mabrey DM Jacobs BL Lincoln HC You JS Hornberger TA The role of skeletal muscle mTOR in the regulation of mechanical load-induced growth J Physiol 2011 589 5485 5501 21946849 PMC3240886

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    • cites [23] Castets P Ruegg MA MTORC1 determines autophagy through ULK1 regulation in skeletal muscle Autophagy 2013 9 1435 1437 23896646

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Toxins injected into muscles undergo retrograde transport to the neuromuscular junction, deposit in motor neurons, and can contribute to motor neuronal dysfunction.

    “when toxins or other compounds are injected into muscles, the compounds undergo retrograde transport to the neuromuscular junction (105), deposit in motor neurons (11), and sometimes contributes to motor neuronal dysfunction (reviewed in (33, 39).”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [105] Pamphlett R Bayliss A Lead uptake in motor axons Muscle Nerve 1992 15 620 625 1584254

      Not checked in the free run.

    • cites [11] Arvidson B Inorganic mercury is transported from muscular nerve terminals to spinal and brainstem motoneurons Muscle Nerve 1992 15 1089 1094 1383815

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    • cites [33] Deinhardt K Schiavo G Endocytosis and retrograde axonal traffic in motor neurons Biochem. Soc. Symp 2005 139 150 15649138

      Not checked in the free run.

    • cites [39] Garcia ML Fernandez A Solas MT Mitochondria, motor neurons and aging J Neurol. Sci 2013 330 18 26 23628465

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Spinal cord injury or denervation induces large-scale muscle wasting, and denervation is often part of sarcopenia.

    “spinal cord injury or denervation induces large-scale muscle wasting (57, 76, 107, 129, 131, 137), and denervation is a condition often seen as part of sarcopenia.”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [57] Iqbal S Ostojic O Singh K Joseph AM Hood DA Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse Muscle Nerve 2013 48 963 970 23494933 source

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    • cites [76] Lee G Lim JY Frontera WR Apoptosis in young and old denervated rat skeletal muscle Muscle Nerve 2016 27312511

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    • cites [107] Pelletier CA Miyatani M Giangregorio L Craven BC Sarcopenic Obesity in Adults With Spinal Cord Injury: A Cross-Sectional Study Arch. Phys. Med Rehabil 2016 97 1931 1937 27282328

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    • cites [129] Siu PM Alway SE Mitochondria-associated apoptotic signalling in denervated rat skeletal muscle J. Physiol 2005 565 309 323 15774533 PMC1464486

      Not checked in the free run.

    • cites [131] Siu PM Alway SE Deficiency of the Bax gene attenuates denervation-induced apoptosis Apoptosis 2006 11 967 981 16763784 PMC4317263

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    • cites [137] Thakore NP Samantaray S Park S Nozaki K Smith JA Cox A Krause J Banik NL Molecular Changes in Sub-lesional Muscle Following Acute Phase of Spinal Cord Injury Neurochem. Res 2016 41 44 52 26290268 PMC9727651

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  • May combine two claims.

    Premisecitation

    PGC-1α splice variants PGC-1α2, PGC-1α3, and PGC-1α4 stimulate protein synthesis and attenuate UPS activity in cultured myotubes and mouse skeletal muscle.

    “PGC-1α2, PGC-1α3, and PGC-1α4, have been shown to stimulate protein synthesis and attenuate UPS activity in cultured myotubes and mouse skeletal muscle (87, 119).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [87] Martinez-Redondo V Jannig PR Correia JC Ferreira DM Cervenka I Lindvall JM Sinha I Izadi M Pettersson-Klein AT Agudelo LZ Gimenez-Cassina A Brum PC Dahlman-Wright K Ruas JL Peroxisome Proliferator-activated Receptor gamma Coactivator-1 alpha Isoforms Selectively Regulate Multiple Splicing Events on Target Genes J Biol. Chem 2016 291 15169 15184 27231350 PMC4946932

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    • cites [119] Ruas JL White JP Rao RR Kleiner S Brannan KT Harrison BC Greene NP Wu J Estall JL Irving BA Lanza IR Rasbach KA Okutsu M Nair KS Yan Z Leinwand LA Spiegelman BM A PGC-1alpha isoform induced by resistance training regulates skeletal muscle hypertrophy Cell 2012 151 1319 1331 23217713 PMC3520615 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activated SIRT1 deacetylates and activates PGC-1α, promoting mitochondrial synthesis, assembly, growth, and antioxidant production.

    “Activated SIRT1 deacetylates and activates PCG-1α which promotes mitochondria synthesis, assembly, growth and mitochondrial antioxidant production (54).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [54] Hsu CP Odewale I Alcendor RR Sadoshima J Sirt1 protects the heart from aging and stress Biol. Chem 2008 389 221 231 18208353

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of MTORC1 in TSC knockout mouse muscle mimics aging features including loss of muscle mass and strength and attenuated mitophagy.

    “Inhibition of MTORC1 in muscles of tuberous sclerosis complex (TSC) knockout mice, mimic many features of aging. This includes a loss of muscle mass and strength and attenuated mitophagy (23).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [23] Castets P Ruegg MA MTORC1 determines autophagy through ULK1 regulation in skeletal muscle Autophagy 2013 9 1435 1437 23896646

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MuRF-1 and MAFbx expression are lower in muscles of old rats than young adults and unchanged with aging in human vastus lateralis.

    “MuRF-1 and MAFbx expression were reported to be lower in muscles of old rats than young adult rats (35) and not changed with aging in vastus lateralis of humans (145).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [35] Edstrom E Altun M Hagglund M Ulfhake B Atrogin-1/MAFbx and MuRF1 are downregulated in aging-related loss of skeletal muscle J Gerontol. A Biol. Sci Med Sci 2006 61 663 674 16870627

      Not checked in the free run.

    • cites [145] Whitman SA Wacker MJ Richmond SR Godard MP Contributions of the ubiquitin-proteasome pathway and apoptosis to human skeletal muscle wasting with age Pflugers Arch 2005 450 437 446 15952031

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ubiquitin, 26S proteasome, poly-ubiquitinated proteins, MuRF-1 and MAFbx expression are elevated in hindlimb muscles of sarcopenic rats compared with young adults.

    “ubiquitin (17), 26S proteasome, poly-ubiquitinated proteins (3), MuRF-1 and MAFbx expression were all reported to be elevated in hindlimb muscles of sarcopenic rats as compared to young adult animals (3, 30).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [17] Cai D Lee KK Li M Tang MK Chan KM Ubiquitin expression is up-regulated in human and rat skeletal muscles during aging Arch. Biochem. Biophys 2004 425 42 50 15081892

      Not checked in the free run.

    • cites [3] Altun M Besche HC Overkleeft HS Piccirillo R Edelmann MJ Kessler BM Goldberg AL Ulfhake B Muscle wasting in aged, sarcopenic rats is associated with enhanced activity of the ubiquitin proteasome pathway J Biol. Chem 2010 285 39597 39608 20940294 PMC3000941 source

      Not checked in the free run.

    • cites [30] Clavel S Coldefy AS Kurkdjian E Salles J Margaritis I Derijard B Atrophy-related ubiquitin ligases, atrogin-1 and MuRF1 are up-regulated in aged rat Tibialis Anterior muscle Mech. Ageing Dev 2006 127 794 801 16949134

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMPK activation and FOXO transcription factors regulate the UPS and the autophagy-lysosome system.

    “AMPK activation (118) and the Forkhead box class O (FOXO) transcription factor family regulates the ubiquitin proteasome system (UPS), and the autophagy-lysosome system.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [118] Romanello V Guadagnin E Gomes L Roder I Sandri C Petersen Y Milan G Masiero E Del PP Foretz M Scorrano L Rudolf R Sandri M Mitochondrial fission and remodelling contributes to muscle atrophy EMBO J 2010 29 1774 1785 20400940 PMC2876965 source

      Not checked in the free run.

    • cites [72] Koga H Kaushik S Cuervo AM Protein homeostasis and aging: The importance of exquisite quality control Ageing Res. Rev 2011 10 205 215 20152936 PMC2888802

      Not checked in the free run.

    • cites [74] Lecker SH Jagoe RT Gilbert A Gomes M Baracos V Bailey J Price SR Mitch WE Goldberg AL Multiple types of skeletal muscle atrophy involve a common program of changes in gene expression FASEB J 2004 18 39 51 14718385

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High apoptotic signaling, altered autophagy signaling, and elevated UPS activity occur in muscles after spinal cord injury or denervation.

    “High levels of apoptotic signaling (1, 129) and altered autophagy signaling (102, 103) with elevated UPS activity (137) occurs in muscles after spinal cord injury or denervation.”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [1] Adhihetty PJ O'Leary MF Chabi B Wicks KL Hood DA Effect of denervation on mitochondrially mediated apoptosis in skeletal muscle J. Appl. Physiol 2007 102 1143 1151 17122379 source

      Not checked in the free run.

    • cites [129] Siu PM Alway SE Mitochondria-associated apoptotic signalling in denervated rat skeletal muscle J. Physiol 2005 565 309 323 15774533 PMC1464486

      Not checked in the free run.

    • cites [102] O'Leary MF Vainshtein A Carter HN Zhang Y Hood DA Denervation-induced mitochondrial dysfunction and autophagy in skeletal muscle of apoptosis-deficient animals Am. J Physiol Cell Physiol 2012 303 C447 C454 22673615

      Not checked in the free run.

    • cites [103] O'Leary MF Vainshtein A Iqbal S Ostojic O Hood DA Adaptive plasticity of autophagic proteins to denervation in aging skeletal muscle Am. J Physiol Cell Physiol 2013 304 C422 C430 23220115 source

      Not checked in the free run.

    • cites [137] Thakore NP Samantaray S Park S Nozaki K Smith JA Cox A Krause J Banik NL Molecular Changes in Sub-lesional Muscle Following Acute Phase of Spinal Cord Injury Neurochem. Res 2016 41 44 52 26290268 PMC9727651

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SIRT1 deacetylation of FOXO1 and FOXO3a mediates autophagic signaling in muscle cells, and aging attenuates SIRT1, reducing autophagy.

    “Deacetylation of FOXO1 and FOXO3a by SIRT1 (19, 20) mediates autophagic signaling in muscle cells, and aging attenuates SIRT1, which reduces autophagy (134).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [19] Canto C Gerhart-Hines Z Feige JN Lagouge M Noriega L Milne JC Elliott PJ Puigserver P Auwerx J AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity Nature 2009 458 1056 1060 19262508 PMC3616311 source

      Not checked in the free run.

    • cites [20] Canto C Jiang LQ Deshmukh AS Mataki C Coste A Lagouge M Zierath JR Auwerx J Interdependence of AMPK and SIRT1 for metabolic adaptation to fasting and exercise in skeletal muscle Cell Metab 2010 11 213 219 20197054 PMC3616265 source

      Not checked in the free run.

    • cites [134] Tang AH Rando TA Induction of autophagy supports the bioenergetic demands of quiescent muscle stem cell activation EMBO J 2014 33 2782 2797 25316028 PMC4282556

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    High ROS can damage more mitochondria in muscle and neurons and potentially elevate ROS further.

    “High ROS can damage more mitochondria in muscle and neurons (81) and potentially elevate ROS levels even higher.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [81] Maharjan S Oku M Tsuda M Hoseki J Sakai Y Mitochondrial impairment triggers cytosolic oxidative stress and cell death following proteasome inhibition Sci. Rep 2014 4 5896 25077633 PMC4116626

      Not checked in the free run.

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

    Interpretationreasoning

    Discrepancies in MuRF-1 and MAFbx findings may be due to low subject numbers and differences in age and sex.

    “The discrepancy between these studies might be due to variability introduced by a low number of subjects or animals in each study, and perhaps by some differences in the age and sex of the subjects that were studied.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Motor neuron dysfunction and death may converge on mitochondria, and mitochondrial dynamics may regulate neuronal function contributing to accelerated sarcopenia.

    “motor neuron dysfunction and death may converge upon mitochondria, and mitochondrial dynamics may play an important role in regulation of neuronal function that contributes to accelerated sarcopenia.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [61] Jiang Z Wang W Perry G Zhu X Wang X Mitochondrial dynamic abnormalities in amyotrophic lateral sclerosis Transl. Neurodegener 2015 4 14 26225210 PMC4518588

      Not checked in the free run.

    • cites [143] Wang W Zhang F Li L Tang F Siedlak SL Fujioka H Liu Y Su B Pi Y Wang X MFN2 couples glutamate excitotoxicity and mitochondrial dysfunction in motor neurons J Biol. Chem 2015 290 168 182 25416777 PMC4281719

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    PARK7 is an antioxidant protein that limits mitochondrial damage under oxidative stress and regulates skeletal muscle contractile protein synthesis and hypertrophy.

    “PARK7 is an antioxidant protein that limits mitochondrial damage in response to oxidative stress (12) and it regulates skeletal muscle contractile protein synthesis and hypertrophy (149).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [12] Billia F Hauck L Grothe D Konecny F Rao V Kim RH Mak TW Parkinson-susceptibility gene DJ-1/PARK7 protects the murine heart from oxidative damage in vivo Proc. Natl. Acad. Sci U. S. A 2013 110 6085 6090 23530187 PMC3625258

      Not checked in the free run.

    • cites [149] Yu H Waddell JN Kuang S Bidwell CA Park7 expression influences myotube size and myosin expression in muscle PLoS. One 2014 9 e92030 24637782 PMC3956870

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise reduces apoptosis and increases mitophagy.

    “We know that exercise downregulates apoptosis and upregulates mitophagy (4, 52, 128, 146).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [4] Alway SE Bennett BT Wilson JC Sperringer J Mohamed JS Edens NK Pereira SL Green tea extract attenuates muscle loss and improves muscle function during disuse, but fails to improve muscle recovery following unloading in aged rats J. App. Physiol 2015 118 319 330 PMC4312851 25414242

      Not checked in the free run.

    • cites [52] Hood DA Mechanisms of exercise-induced mitochondrial biogenesis in skeletal muscle Appl Physiol Nutr Metab 2009 34 465 472 19448716

      Not checked in the free run.

    • cites [128] Sin TK Yu AP Yung BY Yip SP Chan LW Wong CS Rudd JA Siu PM Effects of long-term resveratrol-induced SIRT1 activation on insulin and apoptotic signalling in aged skeletal muscle Acta Diabetol 2015 52 1063 1075 25959421

      Not checked in the free run.

    • cites [146] Wohlgemuth SE Seo AY Marzetti E Lees HA Leeuwenburgh C Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise Exp. Gerontol 2010 45 138 148 19903516 PMC2829942 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    If the same processes occur in humans as in rodents and non-human mammals, exercise or caloric restriction would increase mitophagy removal of dysfunctional mitochondria, leaving proportionally healthier mitochondria.

    “If the same processes occur in humans as is the case in rodents and non-human mammals (64), exercise, or nutritional intervention such as caloric restriction would also be expected to increase mitophagy removal of dysfunctional mitochondrial, so the mitochondria that remain are proportionally healthier (64).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [64] Joseph AM Malamo AG Silvestre J Wawrzyniak N Carey-Love S Nguyen LM Dutta D Xu J Leeuwenburgh C Adhihetty PJ Short-term caloric restriction, resveratrol, or combined treatment regimens initiated in late-life alter mitochondrial protein expression profiles in a fiber-type specific manner in aged animals Exp. Gerontol 2013 48 858 868 23747682 PMC4550205

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aging causes degradation and reduced availability of LAMP2A in lysosomal membranes, reducing CMA effectiveness.

    “Aging causes degradation and availability of LAMP2A in the lysosomal membranes (69), which reduces the effectiveness of CMA.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Kiffin R Kaushik S Zeng M Bandyopadhyay U Zhang C Massey AC Martinez-Vicente M Cuervo AM Altered dynamics of the lysosomal receptor for chaperone-mediated autophagy with age J Cell Sci 2007 120 782 791 17284523

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aging, mitochondrial damage, and death signaling all negatively affect satellite cells.

    “satellite cells are affected adversely by aging, mitochondrial damage and death signaling (4, 6, 7, 144)”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [4] Alway SE Bennett BT Wilson JC Sperringer J Mohamed JS Edens NK Pereira SL Green tea extract attenuates muscle loss and improves muscle function during disuse, but fails to improve muscle recovery following unloading in aged rats J. App. Physiol 2015 118 319 330 PMC4312851 25414242

      Not checked in the free run.

    • cites [6] Alway SE Myers MJ Mohamed JS Regulation of satellite cell function in sarcopenia Frontiers of Aging Neuroscience 2014 6 1 15 PMC4170136 25295003

      Not checked in the free run.

    • cites [7] Alway SE Pereira SL Edens NK Hao Y Bennett BT β−Hydroxy-β-methylbutyrate (HMB) enhances the proliferation of satellite cells in fast muscles of aged rats during recovery from disuse atrophy Exp. Gerontol 2013 48 973 984 23832076

      Not checked in the free run.

    • cites [144] Wang X Pickrell AM Rossi SG Pinto M Dillon LM Hida A Rotundo RL Moraes CT Transient systemic mtDNA damage leads to muscle wasting by reducing the satellite cell pool Hum. Mol. Genet 2013 22 3976 3986 23760083 PMC3766186

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Endurance and resistance exercise have both been linked to increased mitochondrial biogenesis.

    “Both endurance and resistance exercise have been associated with elevated mitochondrial biogenesis (93, 109).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [93] Menzies KJ Singh K Saleem A Hood DA Sirtuin 1-mediated effects of exercise and resveratrol on mitochondrial biogenesis J Biol. Chem 2013 288 6968 6979 23329826 PMC3591607

      Not checked in the free run.

    • cites [109] Porter C Reidy PT Bhattarai N Sidossis LS Rasmussen BB Resistance Exercise Training Alters Mitochondrial Function in Human Skeletal Muscle Med Sci Sports Exerc 2015 47 1922 1931 25539479 PMC4478283 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Autophagy signals are necessary to achieve aerobic improvements in skeletal muscle.

    “it has been proposed that autophagy signals are necessary to achieve aerobic improvements in skeletal muscle (78).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Lira VA Okutsu M Zhang M Greene NP Laker RC Breen DS Hoehn KL Yan Z Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance FASEB J 2013 27 4184 4193 23825228 PMC4046188 source

      Not checked in the free run.

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

    Premisecitation

    Exercise-induced Pink1 activation of Drp1 could target dysfunctional mitochondria for mitophagy.

    “Exercise-induced Pink1 activation of Drp1 (112) could also target dysfunctional mitochondria for mitophagy.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [112] Pryde KR Smith HL Chau KY Schapira AH PINK1 disables the anti-fission machinery to segregate damaged mitochondria for mitophagy J Cell Biol 2016 213 163 171 27091447 PMC5084273 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of PARK7 reduces mitochondrial dysfunction under oxidative stress, showing a direct link between autophagy and mitochondrial function.

    “Overexpression of PARK7 reduces mitochondrial dysfunction under oxidative stress (142) which shows a direct link between autophagy and mitochondrial function.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [142] Wang B Cai Z Tao K Zeng W Lu F Yang R Feng D Gao G Yang Q Essential control of mitochondrial morphology and function by chaperone-mediated autophagy through degradation of PARK7 Autophagy 2016 1 14 27171370 PMC4968227

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Altered neuronal signaling is due at least in part to high ROS and mitochondrial dysfunction in muscle cells, and neural dysfunction is communicated to muscle cells.

    “we would expect that altered neuronal signaling is due at least in part to high ROS production and mitochondrial dysfunction in the muscle cells, and conversely, that neural dysfunction will be communicated to muscle cells (57, 100).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [57] Iqbal S Ostojic O Singh K Joseph AM Hood DA Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse Muscle Nerve 2013 48 963 970 23494933 source

      Not checked in the free run.

    • cites [100] Muller FL Song W Jang YC Liu Y Sabia M Richardson A Van Remmen H Denervation-induced skeletal muscle atrophy is associated with increased mitochondrial ROS production Am. J. Physiol. Regul. Integr. Comp. Physiol 2007 293 R1159 R1168 17584954

      Not checked in the free run.

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

    Interpretationnone given

    Activation of the proteasome removes cellular material near dysfunctional mitochondria.

    “Proteasome activation leads to removal of cellular contents close to the site of dysfunctional mitochondria”
    Quote in the paperNot a substantial claim
47 of 47

  • The authors state this as an assumption.

    Local mitochondrial damage causes increased mPTP opening.

    “This model assumes that local mitochondrial damage (potentially via ROS, high calcium loads, mtDNA damage etc.) causes increased mPTP opening”

  • The authors state this as an assumption.

    mPTP opening triggers mitochondrial contents to leak into the cytosol.

    “which triggers the contents of the mitochondria to leak to the cytosol.”

  • The authors state this as an assumption.

    Leaked mitochondrial contents initiate intrinsic apoptotic signaling leading to DNA fragmentation and nuclear apoptosis in a localized fiber region.

    “This initiates the intrinsic apoptotic signaling pathway leading to DNA fragmentation and nuclear apoptosis in a localized region of the fiber.”

  • The paper relies on this without support.

    Aging suppression of autophagy activators such as SIRT1 and Mfn2 prevents removal of dysfunctional mitochondria via mitophagy and proteasome digestion.

    “An aging-suppression of autophagy activators like Sirtuin 1 (SIRT1) and Mfn2 or other proteins involved in mitophagy, prevents removal of dysfunctional mitochondria via mitophagy and proteasome digestion.”

  • The paper relies on this without support.

    Fragmented mitochondria have lower respiratory capacity and greater ROS production, increasing susceptibility to release contents and activate the intrinsic caspase apoptotic pathway.

    “Fragmented mitochondria tend to have a lower respiratory capacity, and a greater production of ROS, which increases the susceptibility of mitochondria to release its contents and activate the intrinsic caspase apoptotic pathway.”

  • The paper relies on this without support.

    Aging is associated with high cellular ROS levels, and ROS accumulation induces mPTP opening.

    “aging is associated with high cell levels of ROS and ROS accumulation is an inductor for mPTP opening.”

  • The paper relies on this without support.

    Aging leads to systemic mitochondrial dysfunction throughout the body, possibly caused by high ROS or mtDNA damage accumulation.

    “Although aging induces wide spread systemic mitochondrial dysfunction, perhaps as a result of high ROS or accumulation of mtDNA damage”
7 of 7

Claims other papers make about this one

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Cites

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1 of the 151 references couldn’t be matched to a known paper.

Research works printed but not linked: 1

  1. 2009, Mechanisms of exercise-induced mitochondrial biogenesis in skeletal muscle, Appl. Physiol. Nutr. Metab, 34, 465

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Related

Authors
Alway, S. E., Mohamed, J. S., & Myers, M. J.
Affiliations
West Virginia University (US)
Corresponding author
Alway, Stephen E.
ORCID
Venue
Exercise and Sport Sciences Reviews
Publisher
Ovid Technologies (Wolters Kluwer Health)
Published
2017-04
Volume
45
Issue
2
Pages
58-69
ISSN
  • 0091-6331 (ISSN-L)
  • 1538-3008
DOI
10.1249/jes.0000000000000101
PMC
PMC5357179
OpenAlex
W2576104985
Semantic Scholar
a327c586451d76c3458f3b2dcee83eaa79f8426b
Cited by
153
References
151
Citations by year
2026: 10 · 2025: 24 · 2024: 24 · 2023: 22 · 2022: 17 · 2021: 17 · 2020: 16 · 2019: 13 · 2018: 8 · 2017: 2
FWCI
1.00
Type
journal article
Language
en
Open access
Locations
  • Exercise and Sport Sciences Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • The Research Repository @ WVU (West Virginia University) (submittedVersion)
Funders
  • West Virginia University
  • National Institutes of Health (2p20rr016477-09, 1p30rr032138-01)
  • National Institute of General Medical Sciences (P30GM103488, P20GM103434, U54GM104942)
  • National Center for Research Resources (P30-RR-032138, P20-RR016477, P20RR016440)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
sarcopenia, mitochondrial dysfunction, motor neuron degeneration, signaling pathways, sarcopenia prevention
MeSH terms
Forkhead Box Protein O1, Aging, Animals, Humans, Mitochondria, Muscle, Motor Neurons, Muscular Atrophy, Signal Transduction, Cell Death, Apoptosis, Muscle, Skeletal, Ubiquitin, Sarcopenia, Mitophagy

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 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

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