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Cited by 136Autophagy in Disease and TherapyMuscle Physiology and DisordersGenetics, Aging, and Longevity in Model Organisms

Autophagy and mitophagy flux in young and aged skeletal muscle following chronic contractile activity

Open access
Carter, Heather N., Kim, Yuho, Erlich, Avigail T., Zarrin‐khat, Dorrin, Hood, David A.·2018·The Journal of Physiology
DOI 10.1113/jp275998PMC PMC6092298
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Abstract

Key points: A healthy mitochondrial pool is dependent on the removal of dysfunctional organelles via mitophagy, but little is known about how mitophagy is altered with ageing and chronic exercise. Chronic contractile activity (CCA) is a standardized exercise model that can elicit mitochondrial adaptations in both young and aged muscle, albeit to a lesser degree in the aged group. Assessment of mitophagy flux revealed enhanced targeting of mitochondria for degradation in aged muscle, in contrast to previous theories. Mitophagy flux was significantly reduced as an adaptation to CCA suggesting that an improvement in organelle quality reduces the need for mitochondrial turnover. CCA enhances lysosomal capacity and may ameliorate lysosomal dysfunction in aged muscle. Skeletal muscle exhibits deficits in mitochondrial quality with age. Central to the maintenance of a healthy mitochondrial pool is the removal of dysfunctional organelles via mitophagy. Little is known on how mitophagy is altered with ageing and chronic exercise. We assessed mitophagy flux using colchicine treatment in vivo following chronic contractile activity (CCA) of muscle in young and aged rats. CCA evoked mitochondrial biogenesis in young muscle, with an attenuated response in aged muscle. Mitophagy flux was higher in aged muscle and was correlated with the enhanced expression of mitophagy receptors and upstream transcriptional regulators. CCA decreased mitophagy flux in both age groups, suggesting an improvement in organelle quality. CCA also reduced the exaggerated expression of TFEB evident in aged muscle, which may be promoting the age‐induced increase in lysosomal markers. Thus, aged muscle possesses an elevated drive for autophagy and mitophagy which may contribute to the decline in organelle content observed with age, but which may serve to maintain mitochondrial quality. CCA improves organelle integrity and reduces mitophagy, illustrating that chronic exercise is a modality to improve muscle quality in aged populations.

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Written from the paper’s full text.

TL;DR

In young and aged rat skeletal muscle, chronic contractile activity (CCA) induced mitochondrial biogenesis more strongly in young muscle, while aged muscle showed elevated basal autophagy/mitophagy flux. CCA reduced mitophagy flux in both age groups and lowered exaggerated TFEB in aged muscle, suggesting improved organelle quality.

Key findings

  • Aged muscle had higher basal mitophagy flux: LC3-II IMF flux was 1.6-fold higher than young muscle, and p62 IMF flux was also 1.6-fold higher. CCA decreased LC3-II IMF flux by 40% in young and 24% in aged muscle.
  • CCA induced mitochondrial biogenesis in young muscle (COX activity 1.7-fold; PGC-1α 1.6-fold), but the aged response was attenuated, with no significant PGC-1α increase and lower COX activity than young CCA muscle.
  • Aged muscle showed elevated autophagy/mitophagy markers versus young muscle, including BNIP3 4.8-fold, NIX 4.0-fold, optineurin 2.7-fold, TFEB 2.8-fold, LAMP-2 4.7-fold, and cathepsin D ~3-fold. CCA reduced TFEB in aged muscle and increased LAMP-1 in both age groups.
  • CCA increased optineurin 3.9-fold and BNIP3 1.9-fold in young muscle only; p53 was enriched in aged muscle and increased 1.7-fold with CCA in aged muscle.

Methods

  • Male Fisher 344 Brown Norway F1 hybrid rats were studied: young (5–6 months) and aged (35–36 months). The left tibialis anterior and extensor digitorum longus were stimulated for 3 h/day for 9 consecutive days as CCA, with the contralateral limb as internal control.
  • Autophagy/mitophagy flux was assessed using colchicine (0.4 mg kg−1 day−1) versus vehicle during the last 3 days of CCA; LC3-II and p62 were measured in whole muscle and isolated intermyofibrillar mitochondria by Western blot, alongside respirometry, COX activity, electron microscopy, and histochemistry.
  • Statistics used Student’s t test or two-way ANOVA with Tukey post hoc tests; separate two-way ANOVAs were performed for vehicle- and colchicine-treated young and aged groups with CCA in Figs 4 and 6.

Limitations

  • Stated: unequal group sizes prevented repeated-measures or three-way ANOVA; the authors call for future work on FoxO3/p53 cellular localization and phosphorylation, TFEB localization/phosphorylation, and direct lysosomal function/degradation capacity.
  • Stated/evident: flux calculations rely on colchicine inhibition and isolated organelles as an approximation; electron microscopy observations were qualitative with n = 2; aged mitochondrial adaptation remains controversial.
  • Evident: the study used only male rats and a stimulated CCA model, so generalizability to females, voluntary exercise, or humans is not established.

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

Integrity signals

Registry

Crossref · 10.1113/jp275998

Cites

91 of 91 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 78 cited sources checked · 0 supported · 0 flagged

  • Findingown data
    § Abstract

    Assessment of mitophagy flux revealed enhanced targeting of mitochondria for degradation in aged muscle, in contrast to previous theories.

    “Assessment of mitophagy flux revealed enhanced targeting of mitochondria for degradation in aged muscle, in contrast to previous theories.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    CCA decreased mitophagy flux in both age groups.

    “CCA decreased mitophagy flux in both age groups, suggesting an improvement in organelle quality.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    CCA reduces mitophagy.

    “CCA improves organelle integrity and reduces mitophagy, illustrating that chronic exercise is a modality to improve muscle quality in aged populations.”
    Quote in the paperSubstantial claim
  • Findingnone given
    § Abstract

    CCA enhances lysosomal capacity.

    “CCA enhances lysosomal capacity and may ameliorate lysosomal dysfunction in aged muscle.”
    Quote in the paperSubstantial claim
  • Findingown data
    § Abstract

    CCA evoked mitochondrial biogenesis in young muscle.

    “CCA evoked mitochondrial biogenesis in young muscle, with an attenuated response in aged muscle.”
    • Also stated in: § Results · plain
      “In young animals, CCA induced a 1.7‐fold increase (P < 0.05) in COX activity versus the contralateral muscle (Fig. 1 A).”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: Intact mitochondrial biogenesis is essential to produce and maintain healthy organelles.
  • May combine two claims. 32
  • Classified as probably not a substantial claim. 20
  • The quote only partly states this claim. 1

  • May combine two claims.

    Findingown data
    § Results

    COX activity in young animals following CCA was significantly higher than in aged CON and CCA muscle, by 2-fold and 1.5-fold, respectively.

    “Furthermore, post hoc analysis revealed that COX activity in young animals following CCA was significantly higher than in aged CON and CCA muscle, by 2‐fold and 1.5‐fold, respectively (P < 0.05, Fig. 1 A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    No change in muscle mass was noted following CCA or with colchicine injections in either age group.

    “No change in muscle mass was noted following CCA or with colchicine injections in either age group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Aged animals were significantly larger than the young group and contained a larger fat mass.

    “Aged animals were significantly larger than the young group and contained a larger fat mass (P < 0.05; Table 1), although no changes in food intake were noted.”
    Quote in the paperNot a substantial claim

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

    Findingown data
    § Results

    Aged animals had larger hearts, indicative of modest hypertrophy.

    “Additionally, aged animals had larger hearts, indicative of modest hypertrophy (P < 0.05; Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingnone given
    § Discussion

    The aged cohort of the Fisher 344 Brown Norway Hybrid rat displayed hallmark features of aged muscle, including reduced muscle mass, lower mitochondrial content, decreased respiration and the presence of lipofuscin.

    “The aged cohort of this strain displayed hallmark features of aged muscle, including reduced muscle mass, lower mitochondrial content, decreased respiration and the presence of lipofuscin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    With ageing, the SS layer became notably thinner and less dense.

    “With ageing, the SS layer became notably thinner and less dense”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    Neither CCA nor colchicine had an effect on LC3-I levels in either age group.

    “Neither CCA nor colchicine had an effect on LC3‐I levels in either age group.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    p62 localization to IMF mitochondria was very low in muscle of young animals and accumulated to significantly higher levels on mitochondria from aged muscle.

    “p62 localization to IMF mitochondria was very low in muscle of young animals, and accumulated to significantly higher levels on mitochondria from aged muscle (P < 0.05, Fig. 5 D and E).”
    Quote in the paperSubstantial claim

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

    Findingnone given
    § Results

    IMF p62 flux remained unchanged following CCA in aged muscle.

    “and this remained unchanged following CCA.”
    Quote in the paperNot a substantial claim

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

    Findingown data
    § Methods

    No effect of colchicine was noted on body mass, food intake, heart mass, epididymal fat, TA mass, or EDL mass.

    “No effect of colchicine was noted on these measures.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    CCA in aged animals also induced mitochondrial biogenesis, but the degree of adaptation was reduced compared to young muscle.

    “CCA in aged animals also induced mitochondrial biogenesis, but the degree of adaptation was reduced compared to that observed in young muscle.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Results

    p53 was undetectable in whole muscle extracts of young animals but was significantly enriched in aged muscle.

    “p53 was undetectable in whole muscle extracts of young animals (data not shown), but was significantly enriched in aged muscle.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Results

    CCA increased the thickness of the subsarcolemmal (SS) layer and intermyofibrillar (IMF) density in young skeletal muscle.

    “qualitative electron micrographs of VEH‐treated muscle demonstrated enhanced thickness of the subsarcolemmal (SS) layer (yellow arrow) and the intermyofibrillar (IMF) density (green arrow) following CCA in young animals”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    CCA induced robust mitochondrial biogenesis in young muscle, as shown by elevated COX activity, enhanced respiration, darker SDH and COX staining, and expansion of SS and IMF populations.

    “in our current study we observed a robust induction of mitochondria in young muscle following nine consecutive days of CCA, as demonstrated by elevated COX activity, enhanced respiration, darker SDH and COX histochemical staining and expansion of the SS and IMF populations observed through qualitative electron microscopy.”
    Quote in the paperSubstantial claim

  • The quote only partly states this claim.

    Findingown data
    § Results

    Aged skeletal muscle contained many fibres with much more variable cross-sectional area than young muscle.

    “the aged muscle contained many fibres with much more variable cross‐sectional area”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    The reduced adaptation in aged muscle was evident from attenuated increases in PGC-1α and reduced increases in COX activity compared to young muscle.

    “This was evident from attenuated increases in the key mitochondrial transcriptional coactivator PGC‐1α, along with reduced increases in COX activity, in aged compared to young muscle.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    Qualitative histochemical staining and electron micrography revealed increases in mitochondria following CCA in aged muscle, but to a lesser degree than in younger counterparts.

    “qualitative histochemical staining and electron micrography revealed increases in mitochondria following CCA in aged muscle, but to a lesser degree than in their younger counterparts.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data
    § Discussion

    FoxO3 and p53 were significantly upregulated with age.

    “However, each of these proteins was significantly upregulated with age, in agreement with other studies (Tamilselvan et al. 2007; Ziaaldini et al. 2015; Wagatsuma et al. 2016).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Tamilselvan et al. 2007

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    • cites Wagatsuma et al. 2016

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    Findingown data
    § Discussion

    Parkin exhibited a trend for upregulation with ageing while optineurin remained unchanged with age.

    “Similar to previous results, Parkin exhibited a trend for upregulation with ageing while optineurin, a receptor which is recruited to ubiquitin‐tagged mitochondria subsequent to phosphorylation (Wong & Holzbaur, 2015; Richter et al. 2016), remained unchanged with age.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Wong & Holzbaur, 2015

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    • cites Richter et al. 2016

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    Findingown data
    § Discussion

    In aged muscle, the same response to CCA was not observed, and optineurin was remarkably unresponsive.

    “In aged muscle, the same response to CCA was not observed, and in the case of optineurin, aged muscle was remarkably unresponsive.”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Introduction

    Measures of autophagosome flux are required, and an accepted technique obligates the use of an autophagy-inhibited condition for all experimental conditions, along with corresponding vehicle controls, to allow for the calculation of flux using isolated organelles.

    “Thus, measures of autophagosome flux are required, and an accepted technique for this obligates the use of an autophagy‐inhibited condition for all experimental conditions, along with the corresponding vehicle controls, to allow for the calculation of flux using isolated organelles (Ju et al. 2010).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Ju et al. 2010

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

    Study design and conductnone given
    § Methods

    Respiratory control ratios were assessed to ensure quality of the fibres and mitochondrial respiration.

    “Respiratory control ratios were assessed to ensure quality of the fibres and mitochondrial respiration.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Introduction

    A difficulty in assessing autophagy and mitophagy in vivo is that these are highly dynamic processes, and static measures are often subject to discrepancies in interpretation.

    “A difficultly in assessing autophagy and mitophagy in vivo is that these are highly dynamic processes, and static measures are often subject to discrepancies in interpretation (Klionsky, 2016; Yoshii & Mizushima, 2017).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Klionsky, 2016

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    • cites Yoshii & Mizushima, 2017

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    Premisecitation
    § Introduction

    Intact autophagy is necessary to preserve muscle mass.

    “Through the use of genetic ablation of critical autophagy genes, it has been shown that intact autophagy is necessary to preserve muscle mass (Masiero et al. 2009), and the degeneration of muscle that occurs in the absence of autophagy is reminiscent of the maladaptive changes that occur with ageing (Carnio et al. 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Masiero et al. 2009

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    • Rests on an assumption: The removal of damaged/dysfunctional organelles has a critical role in the health of mitochondria and skeletal muscle.

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

    Study design and conductnone given
    § Methods

    All animal procedures were conducted in strict accordance with the standards set by the Canadian Council on Animal Care and with the approval of York University Animal Care Committee.

    “All animal procedures were conducted in strict accordance with the standards set by the Canadian Council on Animal Care and with the approval of York University Animal Care Committee (YUACC).”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Introduction

    The degeneration of muscle that occurs in the absence of autophagy is reminiscent of the maladaptive changes that occur with ageing.

    “Through the use of genetic ablation of critical autophagy genes, it has been shown that intact autophagy is necessary to preserve muscle mass (Masiero et al. 2009), and the degeneration of muscle that occurs in the absence of autophagy is reminiscent of the maladaptive changes that occur with ageing (Carnio et al. 2014).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Carnio et al. 2014

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    Premisecitation
    § Introduction

    Only one study used an autophagy inhibitor to capture the dynamic turnover of autophagosomes through autophagy, and neither study isolated mitochondria to examine the rate at which mitochondria may be targeted for mitophagy following training.

    “However, only one study used an autophagy inhibitor to capture the dynamic turnover of autophagosomes through autophagy, and neither study isolated mitochondria to examine the rate at which mitochondria may be targeted for mitophagy following training.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Lira et al. 2013

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    • cites Ju et al. 2016

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    Premisecitation
    § Introduction

    Signalling towards nuclear genes encoding mitochondrial proteins (NuGEMPs) is blunted in aged muscle, suggesting that mitochondrial biogenesis remains low in aged muscle.

    “Previous work has detailed that the signalling towards nuclear genes encoding mitochondrial proteins (NuGEMPs) is blunted, suggesting that mitochondrial biogenesis remains low in aged muscle (Ljubicic & Hood, 2009).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Ljubicic & Hood, 2009

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    • Rests on an assumption: Intact mitochondrial biogenesis is essential to produce and maintain healthy organelles.

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

    Premisecitation
    § Introduction

    There is an increased presence of the mitophagy receptor Parkin on isolated organelles from aged skeletal muscle.

    “Furthermore, there is an increased presence of the mitophagy receptor Parkin on isolated organelles (O'Leary et al. 2013).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites O'Leary et al. 2013

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    Premisecitation
    § Abstract

    Chronic contractile activity (CCA) is a standardized exercise model that can elicit mitochondrial adaptations in both young and aged muscle, albeit to a lesser degree in the aged group.

    “Chronic contractile activity (CCA) is a standardized exercise model that can elicit mitochondrial adaptations in both young and aged muscle, albeit to a lesser degree in the aged group.”
    • Also stated in: § Introduction · hedged
      “exercise training may not produce the same magnitude of mitochondrial adaptation in aged muscle when compared to younger cohorts (Carter et al. 2015; Hood et al. 2016)”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Carter et al. 2015

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    • cites Hood et al. 2016

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    Study design and conductown data
    § Methods

    Due to unequal group sizes, repeated measures assessment or a three-way ANOVA was unable to be performed.

    “Due to unequal group sizes, repeated measures assessment or a three‐way ANOVA was unable to be performed.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Premisecitation
    § Introduction

    Exercise training may not produce the same magnitude of mitochondrial adaptation in aged muscle when compared to younger cohorts.

    “Furthermore, while beneficial, exercise training may not produce the same magnitude of mitochondrial adaptation in aged muscle when compared to younger cohorts (Carter et al. 2015; Hood et al. 2016), and controversy on this topic remains (Robinson et al. 2017).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Carter et al. 2015

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    • cites Hood et al. 2016

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    • cites Robinson et al. 2017

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    Premisecitation
    § Introduction

    With engagement in habitual aerobic exercise, expansion of the mitochondrial reticulum and improved integrity of the organelles in skeletal muscle occurs in young, healthy individuals.

    “With engagement in habitual aerobic exercise, expansion of the mitochondrial reticulum and improved integrity of the organelles in skeletal muscle has been well described to occur in young, healthy individuals (Holloszy, 1967; Hoppeler et al. 1985; Menzies et al. 2013).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Holloszy, 1967

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    • cites Menzies et al. 2013

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    Study design and conductnone given
    § Methods

    Animals were randomly assigned to the treatment groups.

    “Animals were randomly assigned to the treatment groups.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Study design and conductcitation
    § Methods

    This duration of colchicine treatment is sufficient to inhibit autophagy for the measurement of flux, yet will not induce myopathy.

    “Moreover, this duration of colchicine treatment is sufficient to inhibit autophagy for the measurement of flux (Ju et al. 2010; Mofarrahi et al. 2013; Vainshtein et al. 2015a, b ), yet will not induce myopathy, which is generally observed with treatments lasting 10 days or greater at the same dosage (Ching et al. 2013).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Ju et al. 2010

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    • cites Mofarrahi et al. 2013

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    • cites Vainshtein et al. 2015a

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    Study design and conductown data
    § Discussion

    Colchicine treatment produces increased vacuolar inclusions within both young and aged muscle without disrupting sarcomere structure.

    “Our preliminary data using electron microscopy indicated that autophagy inhibition through colchicine treatment produces an increased level of vacuolar inclusions within both young and aged muscle, as expected, but no disruption in sarcomere structure which might limit muscle contractility (H. N. Carter, Y. Kim, A. T. Erlich, D. Zarrin‐khat and D. A. Hood, unpublished observations).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation
    § Discussion

    Colchicine disrupts microtubules and impairs the ability of autophagosomes to travel to the lysosome for fusion and degradation.

    “Colchicine disrupts microtubules and impairs the ability of autophagosomes to travel to the lysosome for fusion and degradation of their sequestered contents (Amenta et al. 1977; Ju et al. 2010).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Amenta et al. 1977

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    • cites Ju et al. 2010

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    Premisecitation
    § Discussion

    Previous studies utilizing this model have characterized selected dysfunctional properties of mitochondria, including increased ROS production and greater apoptotic susceptibility.

    “previous studies utilizing this model have characterized selected dysfunctional properties of mitochondria, including increased ROS production and greater apoptotic susceptibility (Chabi et al. 2008; Ljubicic et al. 2009).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chabi et al. 2008

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    • cites Ljubicic et al. 2009

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

    Premisecitation
    § Discussion

    Autophagy occurs at low levels basally and is upregulated with a variety of stimuli, including acute exercise.

    “Autophagy occurs at low levels basally, and is known to be upregulated with a variety of stimuli, including acute exercise (He et al. 2012; Vainshtein et al. 2015b).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites He et al. 2012

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    • cites Vainshtein et al. 2015b

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  • May combine two claims.

    Interpretationreasoning
    § Discussion

    CCA promotes a corrective phenotype to both mitochondria and lysosomes in aged muscle.

    “suggesting that CCA promotes a corrective phenotype to both mitochondria and lysosomes in aged muscle.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: TFEB is the master regulator of lysosomal biogenesis.

  • May combine two claims.

    Premisecitation
    § Discussion

    Exercise training or chronic contractile activity improve mitochondrial function, leading to reduced ROS signalling and AMPK activation under conditions of respiratory dysfunction.

    “It is known that under a variety of conditions in which respiratory dysfunction exists, exercise training or chronic contractile activity have led to an improvement in mitochondrial function, leading to reduced ROS signalling and AMPK activation (Taivassalo et al. 2001; Adhihetty et al. 2009; Ljubicic et al. 2009; Carter & Hood, 2012; Conley et al. 2013; Menzies et al. 2013).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Taivassalo et al. 2001

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    • cites Adhihetty et al. 2009

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    • cites Ljubicic et al. 2009

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

    Premisecitation
    § Discussion

    Prior reports have identified an increase in Beclin 1 following both acute and chronic exercise, though some opposing results have also been documented.

    “Previous reports have identified an increase in Beclin 1 following both acute and chronic exercise (He et al. 2012; Ju et al. 2016), but some opposing results have also been documented (McMillan et al. 2015; Mejías‐Peña et al. 2016; Kim & Hood, 2017).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites He et al. 2012

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    • cites Ju et al. 2016

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    • cites McMillan et al. 2015

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

    Interpretationreasoning
    § Discussion

    The overburdened lysosomes in aged skeletal muscle result in the formation of lipofuscin granules.

    “resulting in the formation of lipofuscin granules.”
    Quote in the paperNot a substantial claim

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

    Interpretationcitation
    § Discussion

    p53 may contribute to the production of new organelles with exercise.

    “p53 has also been demonstrated to exert a role in mitochondrial biogenesis with exercise (Saleem et al. 2009; Saleem & Hood, 2013), thus the enhanced expression with ageing and CCA may also contribute to the production of new organelles with exercise.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Saleem et al. 2009

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    • cites Saleem & Hood, 2013

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    Interpretationreasoning
    § Discussion

    In aged skeletal muscle, lysosomes are overburdened and may become unable to process incoming cargo.

    “suggests that the lysosomes are overburdened and may become unable to process the incoming cargo”
    Quote in the paperSubstantial claim

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

    Premisecitation
    § Discussion

    In acute exercise, Beclin 1 association with Bcl-2 decreases within 30 min despite a rise in total Beclin 1 protein.

    “He and colleagues (2012) observed a decreased association of Beclin 1 with Bcl‐2 within 30 min of acute exercise, despite a rise in total protein levels of Beclin 1.”
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    • cites He et al. 2012

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46 of 46

  • The paper relies on this without support.

    A healthy mitochondrial pool is dependent on the removal of dysfunctional organelles via mitophagy.

    “A healthy mitochondrial pool is dependent on the removal of dysfunctional organelles via mitophagy, but little is known about how mitophagy is altered with ageing and chronic exercise.”
    “Central to the maintenance of a healthy mitochondrial pool is the removal of dysfunctional organelles via mitophagy.”

  • The paper relies on this without support.

    Intact mitochondrial biogenesis is essential to produce and maintain healthy organelles.

    “While intact mitochondrial biogenesis is essential to produce/maintain healthy organelles, the removal of damaged/dysfunctional organelles also has a critical role in the health of mitochondria and skeletal muscle.”

  • The paper relies on this without support.

    The removal of damaged/dysfunctional organelles has a critical role in the health of mitochondria and skeletal muscle.

    “While intact mitochondrial biogenesis is essential to produce/maintain healthy organelles, the removal of damaged/dysfunctional organelles also has a critical role in the health of mitochondria and skeletal muscle.”

  • The paper relies on this without support.

    Advancing age causes a loss of muscle mass and performance.

    “With advancing age, there is a loss of muscle mass and performance.”

  • The paper relies on this without support.

    Little research has focused on the selective removal of organelles through mitophagy.

    “Nonetheless, little research has focused on the selective removal of organelles through mitophagy, a process also critical to maintaining organelle and muscle integrity.”

  • The paper relies on this without support.

    TFEB is the master regulator of lysosomal biogenesis.

    “the master regulator of lysosomal biogenesis, TFEB”

  • The paper relies on this without support.

    Beclin 1 is an essential regulator of the core autophagy machinery.

    “Beclin 1, an essential regulator of the core autophagy machinery”
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Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Optineurin is described as unchanged with age despite a reported increase

    Major

    The discussion says optineurin remained unchanged with age, but the results report that optineurin in aged control muscle was 2.7-fold higher than in young control muscle, with P < 0.05.

1 of 1

Cites

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1 of the 92 references couldn’t be matched to a known paper.

Cited by

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Related

Authors
Carter, H. N., Kim, Y., Erlich, A. T., Zarrin‐khat, D., & Hood, D. A.
Affiliations
  • York University (CA)
  • Muscle Health Research Centre, School of Kinesiology and Health Science York University Toronto Ontario M3J 1P3 Canada
Corresponding author
Hood, David A.
ORCID
Venue
The Journal of Physiology
Publisher
Wiley
Published
2018-07-03
Volume
596
Issue
16
Pages
3567-3584
ISSN
  • 0022-3751 (ISSN-L)
  • 1469-7793
DOI
10.1113/jp275998
PMC
PMC6092298
OpenAlex
W2888023575
Semantic Scholar
65e39cd3543ba68a3e8d6d1916d5fb79a0bc3f93
Cited by
136
References
92
Citations by year
2026: 8 · 2025: 12 · 2024: 12 · 2023: 18 · 2022: 19 · 2021: 27 · 2020: 20 · 2019: 13 · 2018: 7
FWCI
13.07
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • The Journal of Physiology (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
Canadian Institutes of Health Research (FRN‐89930)
Topics
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
mitophagy, autophagy, skeletal muscle aging, mitochondrial quality control, mitochondrial biogenesis, TFEB, lysosomal dysfunction, mitophagy receptors, exercise adaptation, organelle turnover
MeSH terms
Aging, Animals, Autophagy, Chronic Disease, Lysosomes, Male, Mitochondria, Muscle, Muscle Contraction, Physical Conditioning, Animal, Rats, Inbred F344, Signal Transduction, Biomarkers, Muscle, Skeletal, Rats, 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 2026-10-06.

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

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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