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Cited by 84Muscle Physiology and DisordersNutrition and Health in AgingAutophagy in Disease and Therapy

Lifelong Aerobic Exercise Alleviates Sarcopenia by Activating Autophagy and Inhibiting Protein Degradation via the AMPK/PGC-1α Signaling Pathway

Open access
Liang, Jiling, Zhang, Hu, Zeng, Zhengzhong, Wu, Liangwen, Zhang, Ying, Guo, Yanju, Lv, Jun, Wang, Cenyi +2 more·2021·Metabolites
DOI 10.3390/metabo11050323PMC PMC8157243
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Abstract

Sarcopenia is an aging-induced syndrome characterized by a progressive reduction of skeletal muscle mass and strength. Increasing evidence has attested that appropriate and scientific exercise could induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular dystrophy. As a publicly recognized strategy for extending lifespan and improving the health of the elderly, the underlying mechanisms of lifelong regular aerobic exercise for the prevention of sarcopenia have not been fully elucidated. To explore the role of lifelong aerobic exercise in the beneficial regulation of autophagic signaling pathways in senescent skeletal muscle, the natural aging mice were used as the sarcopenia model and subjected to lifelong treadmill running to evaluate corresponding parameters related to skeletal muscle atrophy and autophagic signaling pathways. Compared with the young control mice, the aged mice showed a significant reduction in skeletal muscle mass, gastrocnemius muscle weight/body weight (GMW/BW) ratio, and cross-sectional areas (CSA) of skeletal muscle fibers (p < 0.01). In contrast, lifelong aerobic exercise effectively rescued these reduced biomarkers associated with muscle atrophy. Moreover, as shown in the activated AMPK/PGC-1α signaling pathway, lifelong aerobic exercise successfully prevented the aging-induced impairment of the ubiquitin-proteasome system (UPS), excessive apoptosis, defective autophagy, and mitochondrial dysfunction. The exercise-induced autophagy suppressed the key regulatory components of the UPS, inhibited excessive apoptosis, and optimized mitochondrial quality control, thereby preventing and delaying aging-induced skeletal muscle atrophy.

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Written from the paper’s full text.

TL;DR

Lifelong moderate aerobic exercise in aged ICR mice alleviated sarcopenia by activating AMPK/PGC-1α signaling, inducing autophagy, suppressing ubiquitin-proteasome protein degradation and excessive apoptosis, and improving mitochondrial quality control. The exercise rescued age-related declines in muscle mass, fiber cross-sectional area, mitochondrial function, and oxidative stress markers.

Key findings

  • Aged control mice showed reduced gastrocnemius muscle weight/body weight ratio (p < 0.001), decreased skeletal muscle fiber cross-sectional area (p < 0.01), lower citrate synthase activity (p < 0.05), lower serum SOD activity (p < 0.01), and higher muscle MDA content (p < 0.001); lifelong aerobic exercise rescued these changes (GMW/BW p < 0.01; CSA p < 0.05; CS p < 0.001; SOD p < 0.01; MDA p < 0.001).
  • Exercise suppressed protein degradation markers: aged mice had increased Atrogin-1/MAFbx (p < 0.001), MuRF1 (p < 0.01), and myostatin (p < 0.001), while exercised mice had reduced Atrogin-1/MAFbx (p < 0.01), MuRF1 (p < 0.001), and myostatin (p < 0.001); exercise also suppressed age-related increases in p-AktSer473/Akt (p < 0.01) and p-mTORSer2448/mTOR (p < 0.001).
  • Exercise activated autophagy and inhibited apoptosis: aged mice had decreased Beclin1 and LC3-II/LC3-I ratio (p < 0.001) and increased p62 (p < 0.01), while exercised mice had increased Beclin1 and LC3-II/LC3-I ratio (p < 0.001) and decreased p62 (p < 0.001); aged mice had increased Bax and cleaved caspase-3 (p < 0.001) and decreased Bcl-2 (p < 0.05), while exercised mice had decreased Bax (p < 0.001), decreased cleaved caspase-3 (p < 0.05), and increased Bcl-2 (p < 0.01).
  • Exercise improved mitochondrial quality control via AMPK/PGC-1α: aged mice had reduced PGC-1α and p-AMPKThr172/AMPK (p < 0.001), COXIV (p < 0.01), PINK1 (p < 0.01), Parkin (p < 0.001), Mfn2 (p < 0.01), and Drp1 (p < 0.001); lifelong aerobic exercise upregulated these mitochondrial biogenesis, mitophagy, and dynamics proteins.

Methods

  • Three-month-old male ICR mice were randomly divided into a naturally aged control group (OC; n = 10) and a lifelong aerobic exercise group (OE; n = 10), with exercise continuing until 17 months of age; another 10 three-month-old male ICR mice served as the young control group (YC).
  • OE mice underwent 1 week of treadmill habituation, then treadmill running at 12 m/min for 60 min/day, 5 days/week for 55 consecutive weeks until 17 months old.
  • Gastrocnemius muscle was assessed by GMW/BW ratio, HE staining for fiber cross-sectional area, transmission electron microscopy for mitochondrial number/ultrastructure, citrate synthase activity, serum SOD and muscle MDA assays, and Western blotting for UPS, Akt/mTOR, autophagy, apoptosis, AMPK/PGC-1α, mitophagy, and mitochondrial dynamics proteins; statistical analysis used one-way ANOVA or Kruskal-Wallis with p < 0.05.

Limitations

  • The paper states that further studies are needed to explore a definite link between Akt and mTOR phosphorylation, insulin signaling, anabolic resistance, and muscle mass in skeletal muscle of older animals.
  • Evident from the text: the study used only male ICR mice, with n = 10 per group for main outcomes and n = 3 per group for histology/TEM, so findings may not generalize to females or humans.
  • Evident from the text: there is no dedicated limitations section, and the study does not compare exercise modes, intensities, or durations; causal inference is limited to molecular associations in this animal model.

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

Integrity signals

Registry

Crossref · 10.3390/metabo11050323

Cites

54 of 54 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 46 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Lifelong aerobic exercise rescued GMW/BW ratio in aged mice compared with OC (p < 0.01).

    “In contrast, the GMW/BW ratio of the mice from the lifelong aerobic exercise (OE) group showed considerable rescuing upon lifelong aerobic exercise intervention when compared with that from the OC group (p < 0.01).”
    Quote in the paperSubstantial claim
  • Findingown data

    Aged mice had significantly lower number of mitochondria in skeletal muscle than YC (p < 0.01).

    “Besides, a significantly lower number of mitochondria in the skeletal muscle were observed in the mice from the OC group when compared with the YC group (p < 0.01, Figure 2B).”
    Quote in the paperSubstantial claim
  • Findingown data

    Compared with young control, naturally aged mice had significantly decreased GMW/BW ratio and atrophic symptoms, indicating senescence-induced reduction of skeletal muscle mass (p < 0.001).

    “Compared with the youth control (YC) group, the mice from the naturally aged (OC) group demonstrated a significantly decreased GMW/BW ratio and obvious atrophic symptoms of the skeletal muscle, indicating senescence-induced reduction of skeletal muscle mass in mice (p < 0.001).”
    Quote in the paperSubstantial claim
  • Findingown data

    In skeletal muscle at the aging state, mitochondrial dysfunction is present.

    “our results further confirmed that mitochondrial dysfunction and the AMPK/PGC-1α signaling pathway is significantly inhibited in skeletal muscle at the aging state.”
    Quote in the paperSubstantial claim
  • Findingown data

    Mitophagy-related proteins PINK1 (p < 0.01) and Parkin (p < 0.001) were significantly decreased in skeletal muscle of aged mice.

    “Besides, the mitophagy-related proteins such as PINK1 (p < 0.01) and Parkin (p < 0.001) were also significantly decreased in the skeletal muscle of the aged mice (Figure 6C,D).”
    Quote in the paperSubstantial claim
  • May combine two claims. 40
  • The quote only partly states this claim. 5
  • Classified as probably not a substantial claim. 18

  • May combine two claims.

    Findingown data

    Compared with YC, aged mice had decreased CSA of skeletal muscle fibers (p < 0.01) and increased irregular fibers/nucleus aggregation, suggesting aging-induced degeneration.

    “Compared with the YC group, the skeletal muscle of the mice from the OC group showed more atrophic fibers as manifested by the decreased cross-sectional areas (CSA) of skeletal muscle fibers (p < 0.01) and the increased number of skeletal fibers with irregular shapes, as well as the frequent nucleus aggregation (Figure 1A), suggesting that aging-induced degeneration of the skeletal muscle.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    SOD activity in serum was significantly decreased in OC vs YC (p < 0.01) and rescued by lifelong aerobic exercise (p < 0.01).

    “SOD activity in serum of the mice from the OC group was significantly decreased relative to that of the mice in the YC group (p < 0.01, Figure 3B), which was successfully rescued upon lifelong aerobic exercise intervention (p < 0.01).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    TEM revealed disordered myofilaments, large vacuoles, and swollen/abnormally shaped mitochondria in skeletal muscle of OC vs YC.

    “The evaluation based on transmission electron microscope (TEM) revealed a disordered arrangement of myofilaments, a large number of vacuoles with different sizes, and the swollen and abnormally shaped mitochondria in the skeletal muscle of the mice from the OC group when compared with those in the mice from the YC group (Figure 2A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    CS activity in skeletal muscle was significantly reduced in OC vs YC (p < 0.05); lifelong aerobic exercise stimulated increase of CS activity (p < 0.001).

    “Compared with the YC group, the CS activity in skeletal muscle of the mice from the OC group was significantly reduced (p < 0.05); in contrast, lifelong aerobic exercise stimulated the increase of CS activity (p < 0.001, Figure 3A).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MDA content in gastrocnemius muscle was markedly increased in OC vs YC (p < 0.001) and significantly reduced in OE vs OC (p < 0.001).

    “When MDA content in gastrocnemius muscle was compared between OC and YC groups, a marked increase was observed in the OC group (p < 0.001). However, the MDA level in the gastrocnemius muscle of the mice from the OE group exhibited a significant reduction when compared with the OC group (p < 0.001, Figure 3C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Lifelong aerobic exercise decreased atrophic fibers/migrated nuclei and enlarged CSA (p < 0.05) in aged mice.

    “In contrast, the obviously decreased number of atrophic fibers and migrated nuclei, and the enlarged CSA of skeletal muscle fibers (p < 0.05, Figure 1B) were observed in the mice subjected to lifelong aerobic exercise.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    OE mice had ordered myofilaments, large number of normal mitochondria (p < 0.05), and accumulation of autophagosomes.

    “The skeletal muscle of the mice from the OE group had an ordered arrangement of myofilaments, a large number of normal mitochondria (p < 0.05), and an accumulation of autophagosomes.”
    Quote in the paperSubstantial claim

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    In OE, Beclin1 (p < 0.001) and LC3-II/LC3-I ratio (p < 0.001) were significantly up-regulated, and p62 was significantly down-regulated (p < 0.001).

    “Consistent with these findings, we observed an increased Beclin1 and LC3-II/LC3-I ratio and reduced p62 in the mice upon lifelong aerobic exercise intervention.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In aged mice, expression of PGC-1α (p < 0.001), p-AMPKThr172/AMPK ratio (p < 0.001), and COXIV (p < 0.01) were significantly reduced in sarcopenic muscle.

    “Our results identified the significantly reduced expression of PGC-1α (p < 0.001) and p-AMPKThr172/AMPK ratio (p < 0.001), as well as mitochondrial respiratory chain key protease cytochrome C oxidase subunit IV (COXIV) (p < 0. 01) associated with mitochondrial biogenesis in the sarcopenic muscle of the aged mice (Figure 6A,B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    In OC, pro-apoptotic Bax (p < 0.001) and cleaved caspase-3 (p < 0.001) were significantly increased, and anti-apoptotic Bcl-2 was significantly decreased (p < 0.05).

    “In the present study, as the central modulators of intrinsic apoptosis, the expression of pro-apoptotic biomarkers such as Bax (p < 0.001) and cleaved caspase-3 (p < 0.001) in the sarcopenic muscle of the mice from the OC group was significantly increased, and the expression of an anti-apoptotic biomarker such as Bcl-2 was significantly decreased (p < 0.05).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Aging increased p-AktSer473/Akt (p < 0.05) and p-mTORSer2448/mTOR (p < 0.001) in skeletal muscle.

    “In contrast, protein anabolic factors for promoting protein synthesis via the Akt/mTOR signaling pathway in aging process of skeletal muscle could be up-regulated, as shown in the increased p-AktSer473/Akt (p < 0.05) and p-mTORSer2448/mTOR (p < 0.001);”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Compared with YC, expression of Beclin1 and LC3-II/LC3-I ratio in OC was significantly decreased (p < 0.001), and p62 was markedly increased (p < 0.01).

    “Compared with the YC group, the expression of Beclin1 and LC3-II/LC3-I ratio in the sarcopenic muscle of the mice from the OC group was significantly decreased (p < 0.001), and the expression level of p62 was markedly increased (p < 0.01).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Lifelong aerobic exercise decreased Bax (p < 0.001) and cleaved caspase-3 (p < 0.05), and increased Bcl-2 (p < 0.01) in skeletal muscle of OE.

    “Nevertheless, lifelong aerobic exercise notably attenuated apoptotic cell death, as shown by a significant decrease in the expression of Bax (p < 0.001) and cleaved caspase-3 (p < 0.05), and an increase in the expression of Bcl-2 (p < 0.01) in the skeletal muscle of the mice from the OE group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Atrogin-1/MAFbx (p < 0.001), MuRF1 (p < 0.01), myostatin (p < 0.001), and ubiquitinated protein were up-regulated in sarcopenic muscle of OC vs YC.

    “Our findings suggested that Atrogin-1/MAFbx (p < 0.001), MuRF1 (p < 0.01) and myostatin (p < 0.001) associated with the ubiquitin-proteasome system (UPS) and ubiquitinated protein in the sarcopenic muscle of the mice from the OC group were extraordinarily up-regulated when compared with the YC group.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Lifelong aerobic exercise increased number of mitochondria and improved their structure, possibly partially due to induction of autophagy.

    “These findings portrayed that lifelong aerobic exercise increased the number of mitochondria and improved their structure, which could be partially due to the induction of autophagy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Aerobic exercise can increase energy production by mitochondria and capillary density of skeletal muscle, thus promoting oxygen consumption and cellular homeostasis, and delaying skeletal muscle atrophy.

    “Aerobic exercise, as a repeated exercise involving a large number of large muscle groups, can increase energy production by mitochondria and capillary density of skeletal muscle, thus promoting oxygen consumption and cellular homeostasis, and delaying skeletal muscle atrophy [17].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [17] Starnes, J.W., Parry, T.L., O’Neal, S.K., Bain, J.R., Muehlbauer, M.J., Honcoop, A., Ilaiwy, A., Christopher, P.M., Patterson, C., and Willis, M.S. (2017). Exercise-induced alterations in skeletal muscle, heart, liver, and serum metabolome identified by non-targeted metabolomics analysis. Metabolites, 7. source

      Not checked in the free run.

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

    Premisecitation

    Both resistance and aerobic exercise can activate autophagic signaling in aged skeletal muscle.

    “Importantly, both exercise methods can activate autophagic signaling in the aged skeletal muscle [15].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [15] Lira, 2013, Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance, FASEB J. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Lifelong aerobic exercise rescued declined CSA and repaired damaged textural structure of skeletal muscle fibers in aged mice.

    “Thus, lifelong aerobic exercise effectively rescued the declined CSA and repaired the damaged textural structure of skeletal muscle fibers in aged mice.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Lifelong aerobic exercise effectively improved SI value and prevented mass decline of skeletal muscle caused by aging.

    “This result suggested that lifelong aerobic exercise effectively improved the SI value of the aged mice and prevented the mass decline of skeletal muscle caused by aging (Table 1).”
    Quote in the paperSubstantial claim

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

    Premisecitation

    A sedentary lifestyle is a novel risk factor for healthy living.

    “A growing body of studies has documented that a sedentary lifestyle is a novel risk factor for healthy living [11,12].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [11] De Rezende, L.F., Rey-López, J.P., Matsudo, V.K., and do Carmo Luiz, O. (2014). Sedentary behavior and health outcomes among older adults: A systematic review. BMC Public Health, 14. source

      Not checked in the free run.

    • cites [12] Luan, 2019, Exercise as a prescription for patients with various diseases, J. Sport Health Sci. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMPK can slow down the aging process by regulating diverse signaling pathways and is a therapeutic target for aging-induced skeletal muscle atrophy.

    “As a key regulator of mitochondrial biogenesis, AMPK can slow down the aging process by regulating diverse signaling pathways, and has been identified as a therapeutic target for aging-induced skeletal muscle atrophy [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Herzig, 2018, AMPK: Guardian of metabolism and mitochondrial homeostasis, Nat. Rev. Mol. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Resistance exercise mainly improves quality and strength of skeletal muscle, while aerobic exercise plays a crucial role in maintaining maximum aerobic capacity and cellular homeostasis of aging skeletal muscle.

    “There is irrefutable evidence that the main role of resistance exercise is to improve the quality and strength of skeletal muscle, while aerobic exercise plays a crucial role in maintaining the maximum aerobic capacity and cellular homeostasis of the aging skeletal muscle [14].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [14] Landi, 2014, Exercise as a remedy for sarcopenia, Curr. Opin. Clin. Nutr. Metab. Care

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Appropriate and scientific exercise can induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular dystrophy.

    “Increasing evidence has attested that appropriate and scientific exercise could induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular dystrophy.”
    • Also stated in: § 1. Introduction · plain
      “the appropriate functional status of autophagy plays a vital role in the regulation of skeletal muscle mass and maintaining cellular homeostasis under degrading conditions [4,5].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [4] Carter, 2018, Autophagy and mitophagy flux in young and aged skeletal muscle following chronic contractile activity, J. Physiol. source

      Not checked in the free run.

    • cites [5] Liang, 2020, Regulatory role of exercise-induced autophagy for sarcopenia, Exp. Gerontol. source

      Not checked in the free run.

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

    Premisecitation

    Activation of Akt/mTOR signaling pathway facilitates growth of skeletal muscle.

    “On the other hand, it is well accepted that the activation of the Akt/mTOR signaling pathway facilitates the growth of skeletal muscle [29].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [29] Sandri, 2008, Signaling in muscle atrophy and hypertrophy, Physiology. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Lifelong aerobic exercise suppressed apoptotic signaling and improved anti-apoptotic capacity of aging skeletal muscle.

    “Therefore, lifelong aerobic exercise could adequately suppress apoptotic signaling and improve anti-apoptotic capacity of the aging skeletal muscle (Figure 5C,D).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Excessive apoptosis can lead to declined function of autophagy and cellular degradation, thereby inducing skeletal muscle atrophy and myopathies.

  • May combine two claims.

    Interpretationown data

    Aging increased p-AktSer473 and p-mTORSer2448, indicating common anabolic resistance might occur in senile muscular atrophy.

    “To our surprise, our results suggested that aging could increase the expression of p-AktSer473 and p-mTORSer2448, indicating that common anabolic resistance might occur in senile muscular atrophy [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Francaux, M., Demeulder, B., Naslain, D., Fortin, R., Lutz, O., Caty, G., and Deldicque, L. (2016). Aging reduces the activation of the mTORC1 pathway after resistance exercise and protein intake in human skeletal muscle: Potential role of REDD1 and impaired anabolic sensitivity. Nutrients, 8. source

      Not checked in the free run.

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

    Premisecitation

    After 8 weeks of treadmill running, down-regulation of Beclin1 and Atg7 in aged rats caused by aging was offset, and quality of skeletal muscle improved.

    “Another study has also documented that after 8 weeks of treadmill running, the down-regulation of Beclin1 and Atg7 in aged rats caused by aging was offset, and the quality of skeletal muscle was also improved effectively [36].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Kim, 2013, Autophagic response to exercise training in skeletal muscle with age, J. Physiol. Biochem. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Lifelong aerobic exercise offset aging-induced functional reduction of mitochondria, possibly due to improvement of mitochondrial content and inhibition of oxidative stress.

    “From these data, it could be concluded that lifelong aerobic exercise could offset aging-induced functional reduction of mitochondria, which may be due to the improvement of mitochondrial content, and corresponding inhibition of oxidative stress.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Lifelong aerobic exercise activated autophagy or rescued abnormal functional status of autophagy in skeletal muscle of aged mice.

    “indicating that lifelong aerobic exercise successfully activated autophagy or rescued the abnormal functional status of autophagy in skeletal muscle of the aged mice.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim.

    Premisecitation

    AMPK can maintain stability of energy state by sensing changes in intracellular AMP/ATP ratio, thus changing expression of downstream proteins and regulating energy production and consumption.

    “AMPK, as a conserved serine/threonine protein kinase and a crucial regulator of metabolic energy sensors, can maintain the stability of the energy state by sensing the changes in intracellular AMP/ATP ratio, thus changing the expression of its downstream proteins and regulates the energy production and consumption in the body [9].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [9] Herzig, 2018, AMPK: Guardian of metabolism and mitochondrial homeostasis, Nat. Rev. Mol. Cell Biol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ICR mice have 50% survival, mean survival, and maximal survival ages of 20, 18, and 31 months, respectively.

    “The 50% survival, mean survival, and maximal survival ages of ICR mice were 20, 18, and 31 months, respectively [25].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [25] Walburg, 1967, Ageing in irradiated and unirradiated germfree ICR mice, Exp. Gerontol. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Atrogin-1 and MuRF1 are most up-regulated proteins under skeletal muscle atrophy and sensitive biomarkers for protein degradation by UPS.

    “Two E3 ubiquitin ligases, including Atrogin-1 and MuRF1, the most up-regulated proteins under the conditions of skeletal muscle atrophy, are the sensitive biomarkers for protein degradation by the UPS [21].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [21] Rom, 2016, The role of E3 ubiquitin-ligases MuRF-1 and MAFbx in loss of skeletal muscle mass, Free Radic. Biol. Med. source

      Not checked in the free run.

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

    Premisecitation

    AMPK stimulates mitochondrial biogenesis through up-regulated PGC-1α.

    “Recently, AMPK has been identified to stimulate mitochondrial biogenesis through up-regulated PGC-1α [44].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [44] Hawley, 2018, Maximizing cellular adaptation to endurance exercise in skeletal muscle, Cell Metab. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise-induced autophagy in skeletal muscle can accelerate elimination/recycling of damaged proteins or misfolded organelles, improve metabolism, and stabilize cellular homeostasis.

    “Exercise-induced autophagy in the skeletal muscle can accelerate the elimination and recycling of damaged proteins or misfolded organelles, improve metabolism, and stabilize the cellular homeostasis of skeletal muscle [34].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [34] Vainshtein, 2016, The regulation of autophagy during exercise in skeletal muscle, J. Physiol.

      Not checked in the free run.

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

    Premisecitation

    PGC-1α is junction between external stimulus signals and internal mitochondrial functions, known as key factor in regulation of mitochondrial biogenesis.

    “PGC-1α is a junction between external stimulus signals and internal mitochondrial functions, known as the key factor in the regulation of mitochondrial biogenesis [10].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Islam, 2018, Coordination of mitochondrial biogenesis by PGC-1α in human skeletal muscle: A re-evaluation, Metabolism source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The 17-month-old natural aging mouse model had SI value significantly lower than young control, indicating aged mice can be regarded as a model of sarcopenia.

    “Thus, we adopted a 17-month-old natural aging mouse model and found that the SI value of the mice in the natural aging model group was significantly lower than that in the young control group, indicating that the aged mice can be regarded as a model of sarcopenia [26].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [26] Baumgartner, 1998, Epidemiology of sarcopenia among the elderly in New Mexico, Am. J. Epidemiol. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Aerobic exercise can enhance autophagic flux, accelerate removal of intracellular damaged proteins and metabolic wastes, thereby promoting structural and functional remodeling of skeletal muscle fibers.

    “This finding suggested that aerobic exercise could enhance autophagic flux, accelerate the removal of intracellular damaged proteins and metabolic wastes in cells, thereby promoting the structural and functional remodeling of skeletal muscle fibers.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Autophagy and apoptosis are mutually inhibited and interrelated biological processes.

  • May combine two claims.

    Interpretationown data

    Lifelong aerobic exercise reduced key regulatory components of UPS signaling pathway and suppressed aging-associated activation of catabolic signaling, thereby postponing muscular atrophy.

    “However, followed by lifelong aerobic exercise, the key regulatory components of the UPS signaling pathway in sarcopenic muscle were reduced, and the aging-associated activation of catabolic signaling was suppressed, thereby postponing muscular atrophy.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Autophagy-dependent signaling transduction defects occur in skeletal muscle at aging state, and appropriate functional status of autophagy plays crucial role in controlling skeletal muscle mass under degradation conditions.

    “Some recent reports have verified autophagy-dependent signaling transduction defects in skeletal muscle at the aging state, and the appropriate functional status of autophagy plays a crucial role in controlling skeletal muscle mass under degradation conditions [32,33].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [32] Russ, 2015, Muscle-specificity of age-related changes in markers of autophagy and sphingolipid metabolism, Biogerontology source

      Not checked in the free run.

    • cites [33] Potes, 2017, Overweight in elderly people induces impaired autophagy in skeletal muscle, Free Radic. Biol. Med. source

      Not checked in the free run.

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

    Premisecitation

    Caloric restriction, exercise intervention, drug administration, and gene therapy can hinder excessive apoptosis of skeletal muscle cells, maintain skeletal muscle mass and integrity, and improve physical performance.

    “On the other hand, caloric restriction, exercise intervention, drug administration, and gene therapy can hinder the excessive apoptosis of skeletal muscle cells, maintain skeletal muscle mass and integrity, and improve its physical performance [41].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [41] Marzetti, 2012, Apoptosis in skeletal myocytes: A potential target for interventions against sarcopenia and physical frailty—A mini-review, Gerontology source

      Not checked in the free run.

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

    Premisecitation

    Under conditions of stress, injury or aging, mitochondrial kinase PINK1 gathers outside the membrane of dysfunctional mitochondria and translocates them into it selectively by phosphorylating and recruiting Parkin, and then ubiquitinates outer mitochondrial membrane proteins such as Mfn1/2 and Drp1 to participate in mitophagy.

    “Under the conditions of stress, injury or aging, mitochondrial kinase PINK1 can gather outside the membrane of dysfunctional mitochondria and translocate them into it selectively by phosphorylating and recruiting Parkin, and then ubiquitinate outer mitochondrial membrane proteins such as mitochondrial fusion key proteins Mfn1/2 and fission key protein Drp1 to participate in mitophagy [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Chen, 2018, Parkin is required for exercise-induced mitophagy in muscle: Impact of aging, Am. J. Physiol. Endocrinol. Metab. source

      Not checked in the free run.

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

    Premisecitation

    Mfn2 deficiency in skeletal muscle exacerbates aging-induced mitochondrial dysfunction in the skeletal muscle associated with the accumulation of mitochondrial damage, indicating Mfn2 deficiency as the important trigger of mitochondrial dysfunction during the aging process.

    “Mfn2 deficiency in skeletal muscle exacerbates aging-induced mitochondrial dysfunction in the skeletal muscle associated with the accumulation of mitochondrial damage, indicating Mfn2 deficiency as the important trigger of mitochondrial dysfunction during the aging process [50]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Sorianello, 2016, Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway, EMBO J. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Mitophagy, as a kind of selective autophagy, can identify and degrade damaged and dysfunctional mitochondria, thus generating a self-protective coping mechanism against mitochondrial dysfunction.

    “mitophagy, as a kind of selective autophagy, can identify and degrade damaged and dysfunctional mitochondria, thus generating a self-protective coping mechanism against mitochondrial dysfunction [47]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [47] Alway, 2017, Mitochondria initiate and regulate sarcopenia, Exerc. Sport Sci. Rev. source

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationreasoning

    Lifelong aerobic exercise suppresses excessive apoptosis.

    “suppress excessive apoptosis”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    The analysis of images was conducted by a single investigator blinded to the samples.

    “The analysis of images was conducted by a single investigator blinded to the samples.”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Interpretationreasoning

    Lifelong aerobic exercise repairs dysfunctional mitochondria.

    “to repair dysfunctional mitochondria”
    Quote in the paperSubstantial claim
    • Rests on an assumption: PINK1/Parkin is one of the components in the classic signaling pathway of mitophagy.

  • May combine two claims.

    Premisecitation

    Exercise-induced mitophagy and increased autophagy/mitophagy flux are significantly attenuated in PGC-1α-deficient mice.

    “This effect is significantly attenuated in PGC-1α-deficient mice [18].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [18] Vainshtein, 2015, Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle, Am. J. Physiol. Cell Physiol. source

      Not checked in the free run.

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

    Premisecitation

    Mitochondrial dynamics regulates mitochondrial number and morphology and plays a crucial role in preventing mitochondrial fragmentation and excessive oxidative stress, thus responding to apoptotic stimuli and mitochondrial quality control.

    “mitochondrial dynamics not only regulates mitochondrial number and morphology, but also plays a crucial role in preventing mitochondrial fragmentation and excessive oxidative stress, thus responding to apoptotic stimuli and mitochondrial quality control [50]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [50] Sorianello, 2016, Mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway, EMBO J. source

      Not checked in the free run.

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

    Study design and conductnone given

    Skeletal muscle fibers in different regions were randomly selected and analyzed in a blinded mode.

    “skeletal muscle fibers in different regions were randomly selected and analyzed in a blinded mode”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim.

    Study design and conductnone given

    Mice were randomly divided into two groups (OC and OE).

    “The mice were randomly divided into two groups: the control group (OC; n = 10; naturally aged model group) and the lifelong aerobic exercise group (OE; n = 10)”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The absence of Drp1 can seriously affect mitochondrial morphology and function, as indicated by volume-enlarged or swollen mitochondria in Drp1 knockout skeletal muscle tissue.

    “recent publications have reported the volume-enlarged or swollen mitochondria in Drp1 knockout skeletal muscle tissue, indicating that the absence of Drp1 can seriously affect mitochondrial morphology and function [51]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [51] Otera, 2011, Molecular mechanisms and physiologic functions of mitochondrial dynamics, J. Biochem. source

      Not checked in the free run.

  • The quote only partly states this claim.

    Interpretationnone given

    Lifelong aerobic exercise inhibits protein ubiquitination.

    “inhibit protein ubiquitination”
    Quote in the paperSubstantial claim

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

    Study design and conductnone given

    At least 150 skeletal muscle fibers were counted in each group for quantification.

    “At least 150 skeletal muscle fibers were counted in each group for quantification”
    Quote in the paperNot a substantial claim

  • The quote only partly states this claim.

    Interpretationreasoning

    Lifelong aerobic exercise improves energy metabolism.

    “improve energy metabolism”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Exercise can remarkably improve the quantity and quality of mitochondria through several adaptive processes, such as mitochondrial dynamics and mitophagy.

    “Exercise can remarkably improve the quantity and quality of mitochondria through several adaptive processes, such as mitochondrial dynamics and mitophagy [49].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [49] Coen, 2018, Mitochondria as a target for mitigating sarcopenia, Front. Physiol. source

      Not checked in the free run.

55 of 55

  • The paper relies on this without support.

    The underlying mechanisms of lifelong regular aerobic exercise for preventing sarcopenia have not been fully elucidated.

    “As a publicly recognized strategy for extending lifespan and improving the health of the elderly, the underlying mechanisms of lifelong regular aerobic exercise for the prevention of sarcopenia have not been fully elucidated.”

  • The paper relies on this without support.

    Myostatin is essential for regulation of skeletal muscle mass and is a negative regulator of skeletal muscle growth.

    “Myostatin is essential for the regulation of skeletal muscle mass and a negative regulator of skeletal muscle growth.”

  • The paper relies on this without support.

    Autophagy and apoptosis are mutually inhibited and interrelated biological processes.

    “In addition, autophagy and apoptosis are highly regulated as the mutually inhibited and interrelated biological processes.”

  • The paper relies on this without support.

    Excessive apoptosis can lead to declined function of autophagy and cellular degradation, thereby inducing skeletal muscle atrophy and myopathies.

    “Excessive apoptosis can lead to the declined function of autophagy and cellular degradation, thereby inducing skeletal muscle atrophy and corresponding myopathies.”

  • The paper relies on this without support.

    Skeletal muscle homeostasis is maintained by a dynamic equilibrium between protein degradation and protein synthesis.

    “Skeletal muscle homeostasis is maintained by a dynamic equilibrium between protein degradation and protein synthesis.”

  • The paper relies on this without support.

    Dysfunctional metabolism in skeletal muscle can accelerate its aging progression.

    “Dysfunctional metabolism in the skeletal muscle can accelerate its aging progression.”

  • The paper relies on this without support.

    Exercise leads to targeting of mitochondria for mitophagy and significantly increased autophagy and mitophagy flux.

    “Exercise can lead to the targeting of mitochondria for mitophagy and significantly increased autophagy and mitophagy flux.”

  • The paper relies on this without support.

    Gradual decrease in physical activity and increase in oxidative stress can cause abnormal accumulation of damaged mitochondria and even initiation of mitochondria-mediated apoptosis.

    “the gradual decrease in physical activity and the increase in oxidative stress can cause abnormal accumulation of damaged mitochondria, and even the initiation of mitochondria-mediated apoptosis”

  • The paper relies on this without support.

    This ultimately causes dysfunctional loss of skeletal muscle in the elderly.

    “This ultimately causes the dysfunctional loss of skeletal muscle in the elderly.”

  • The paper relies on this without support.

    Elevated MDA level, along with decreased SOD and CS activity in aging skeletal muscle, is a clear indicator of oxidative stress.

    “elevated MDA level, along with decreased SOD and CS activity in aging skeletal muscle, is a clear indicator of oxidative stress”

  • The paper relies on this without support.

    PINK1/Parkin is one of the components in the classic signaling pathway of mitophagy.

    “PINK1/Parkin is one of the components in the classic signaling pathway of mitophagy.”

  • The paper relies on this without support.

    Mitochondrial dysfunction, especially metabolic activity, contributes many disorders, including metabolic diseases and aging process.

    “mitochondrial dysfunction, especially metabolic activity, contributes many disorders, including metabolic diseases and aging process”

  • The paper relies on this without support.

    Mfn1/2 and Drp1 cooperate to maintain the dynamic changes of mitochondrial junction structure.

    “Mfn1/2 and Drp1 are cooperated to maintain the dynamic changes of mitochondrial junction structure.”
13 of 13

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Lifelong aerobic exercise in mice activates the AMPK/PGC-1α signaling pathways.

    “The results demonstrate that lifelong aerobic exercise activates the AMPK/PGC-1α signaling pathways”

    From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [18]

  • Lifelong aerobic exercise in mice counteracts age-related decline in mitochondrial fusion and fission biomarkers, enhances the Beclin1 and LC3-II/LC3-I ratio, decreases p62, and promotes mitochondrial biogenesis, improving mitochondrial quality control and delaying the onset of sarcopenia.

    “which helps counteract the age-related decline in mitochondrial fusion and fission biomarkers, enhances the Beclin1 and LC3-II/LC3-I ratio and decreases p62, and effectively promotes mitochondrial biogenesis, thereby improving mitochondrial quality control and delaying the onset of sarcopenia [18].”

    From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [18]

Cites

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Related

Authors
Liang, J., Zhang, H., Zeng, Z., Wu, L., Zhang, Y., Guo, Y., Lv, J., Wang, C., Fan, J., & Chen, N.
Affiliations
  • Wuhan Sports University (CN)
  • Hanshan Normal University (CN)
  • Soochow University (CN)
Corresponding author
  • Fan, Jingjing
  • Chen, Ning
ORCID
Venue
Metabolites
Publisher
MDPI AG
Published
2021-05-18
Volume
11
Issue
5
Pages
323
ISSN
2218-1989 (ISSN-L)
DOI
10.3390/metabo11050323
PMC
PMC8157243
OpenAlex
W3162646626
Semantic Scholar
5475f1e2cc1aceda919d70872b225d12380c891b
Cited by
84
References
58
Citations by year
2026: 17 · 2025: 20 · 2024: 15 · 2023: 20 · 2022: 10 · 2021: 2
FWCI
3.69
Type
journal article
Language
en
Open access
Licence
Locations
  • Metabolites (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
National Natural Science Foundation of China (31571228)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
  • Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
Keywords
sarcopenia, aerobic exercise, autophagy, ubiquitin-proteasome system, protein degradation, skeletal muscle atrophy, aging, treadmill running, mitochondrial quality control, apoptosis, muscle fiber cross-sectional area

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

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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