Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis

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

Exercise induces substantial adaptations in skeletal muscle, including increased muscle mass, improved muscle regeneration and hypertrophy, elevated hormone release, and enhanced mitochondrial function.

“Exercise induces substantial adaptations in skeletal muscle, including increased muscle mass, improved muscle regeneration and hypertrophy, elevated hormone release, and enhanced mitochondrial function.”

May combine two claims.

Exerkines may contribute to skeletal muscle metabolism by ameliorating mitochondrial homeostasis, reducing inflammation, and regulating protein synthesis as a defense against sarcopenia.

“Exerkines (e.g., adipokines, myokines, hepatokines, and osteokines), signaling molecules released in response to exercise training, may potentially contribute to skeletal muscle metabolism through ameliorating mitochondrial homeostasis, reducing inflammation, and regulating protein synthesis as a defense against sarcopenia.”

• AssumptionRests on an assumption: Findings from rodent exercise studies are applicable to human sarcopenia.

May combine two claims.

Regular physical activity or exercise training enhances mitochondrial homeostasis in individuals with sarcopenia and regulates mitophagy, mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial redox biology.

“Engaging in regular physical activity or exercise training, which proves beneficial for enhancing mitochondrial homeostasis in individuals with sarcopenia, significantly regulates mitophagy, mitochondrial biogenesis, mitochondrial dynamics, and mitochondrial redox biology [9,10,11].”

• cites [9] Memme, 2021, Exercise and mitochondrial health, J. Physiol. sourceNot checked yet

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• cites [10] Sorriento, D., Di Vaia, E., and Iaccarino, G. (2021). Physical Exercise: A Novel Tool to Protect Mitochondrial Health. Front. Physiol., 12. sourceNot checked yet

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• cites [11] Zanini, G., De Gaetano, A., Selleri, V., Savino, G., Cossarizza, A., Pinti, M., Mattioli, A.V., and Nasi, M. (2021). Mitochondrial DNA and Exercise: Implications for Health and Injuries in Sports. Cells, 10. sourceNot checked yet

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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].”

• cites [18] Liang, J., Zhang, H., Zeng, Z., Wu, L., Zhang, Y., Guo, Y., Lv, J., Wang, C., Fan, J., and Chen, N. (2021). Lifelong Aerobic Exercise Alleviates Sarcopenia by Activating Autophagy and Inhibiting Protein Degradation via the AMPK/PGC-1α Signaling Pathway. Metabolites, 11. sourceNot checked yet

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Exercise training delays the onset of sarcopenia by maintaining mitochondrial homeostasis, including promoting mitophagy, improving mitochondrial biogenesis, balancing mitochondrial dynamics, and maintaining mitochondrial redox.

“Exercise training effectively delays the onset of sarcopenia by significantly maintaining mitochondrial homeostasis, including promoting mitophagy, improving mitochondrial biogenesis, balancing mitochondrial dynamics, and maintaining mitochondrial redox.”

• AssumptionRests on an assumption: Findings from rodent exercise studies are applicable to human sarcopenia.

May combine two claims.

Exerkine-regulated mechanisms contribute to the maintenance of mitochondrial homeostasis, thereby supporting skeletal muscle metabolism and mitochondrial health.

“These mechanisms contribute to the maintenance of mitochondrial homeostasis, thereby supporting skeletal muscle metabolism and mitochondrial health.”

May combine two claims.

Regular training and daily activity are effective countermeasures to promote hormonal balance, reduce oxidative stress, improve mitochondrial dysfunction, and influence immune function.

“In contrast, regular training and daily activity are effective countermeasures to promote hormonal balance, reduce oxidative stress, improve mitochondrial dysfunction, and influence immune function [15].”

• cites [15] Joseph, 2016, Beneficial effects of exercise on age-related mitochondrial dysfunction and oxidative stress in skeletal muscle, J. Physiol. sourceNot checked yet

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Physical inactivity leads to decreased skeletal muscle protein synthesis, lean tissue mass, and extremity strength, contributing to increased prevalence of sarcopenia.

“Physical inactivity can lead to a decrease in skeletal muscle protein synthesis, lean tissue mass, and extremity strength, contributing to the increased prevalence of sarcopenia [14].”

• cites [14] Kortebein, 2007, Effect of 10 days of bed rest on skeletal muscle in healthy older adults, JAMA sourceNot checked yet

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Elevated mitochondrial Ca2+ interacts with phosphate compounds, damaging the electron transport chain and generating ROS.

“Elevated mitochondrial Ca2+ levels interact with phosphate compounds, resulting in damage to the electron transport chain and the subsequent generation of ROS [31].”

• cites [31] Gong, 2021, Mitochondria-associated membrane-modulated Ca2+ transfer: A potential treatment target in cardiac ischemia reperfusion injury and heart failure, Life Sci. sourceNot checked yet

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Humanin administration promotes autophagy and reduces accumulation of abnormal proteins by activating AMPK upstream of PI3K Class III complex formation, enhancing skeletal muscle health and function.

“Humanin administration promotes autophagy and reduces the accumulation of abnormal proteins by activating AMPK upstream of PI3K Class III complex formation, thereby enhancing skeletal muscle health and function [26].”

• cites [26] Kim, S.J., Devgan, A., Miller, B., Lee, S.M., Kumagai, H., Wilson, K.A., Wassef, G., Wong, R., Mehta, H.H., and Cohen, P. (2022). Humanin-induced autophagy plays important roles in skeletal muscle function and lifespan extension. Biochim. Biophys. Acta Gen. Subj., 1866. sourceNot checked yet

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A high-intensity resistance training regimen significantly decreased expression of pro-inflammatory cytokine receptors and maximized thigh muscle mass and overall lean body mass in older adults.

“significantly decreased the expression of pro-inflammatory cytokine receptors and maximized thigh muscle mass and overall lean body mass in older adults [21].”

• cites [21] Stec, 2017, Randomized, four-arm, dose-response clinical trial to optimize resistance exercise training for older adults with age-related muscle atrophy, Exp. Gerontol. sourceNot checked yet

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High-intensity interval static strength training in aged rats increased muscle fiber volume, prevented atrophy, and improved motor function via the PGC-1α/FNDC5/UCP1 signaling pathway, leading to elevated circulating irisin and stimulating white-to-brown fat conversion.

“a high-intensity interval static strength training (eight weeks) program in aged rats increased the muscle fiber volume, prevented atrophy, and improved motor function via the PGC-1α/FNDC5/UCP1 signaling pathway, leading to elevated circulating levels of irisin and subsequently stimulating the conversion of white fat into brown fat (Figure 1) [22].”

• cites [22] Liu, 2021, Eight Weeks of High-Intensity Interval Static Strength Training Improves Skeletal Muscle Atrophy and Motor Function in Aged Rats via the PGC-1α/FNDC5/UCP1 Pathway, Clin. Interv. Aging sourceNot checked yet

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Resistance exercise enhances autophagy and reduces apoptosis in skeletal muscle of older rats by modulating IGF-1 and its receptors, and downregulating Akt/mTOR and Akt/FOXO3a signaling pathways.

“Resistance exercise (ladder-climbing training, 3 days/week for 9 weeks) has been shown to enhance autophagy and reduce apoptosis in the skeletal muscle of older rats by modulating insulin-like growth factor-1 (IGF-1) and its receptors, as well as the downregulation of Akt/mTOR and Akt/FOXO3a signaling pathways [41].”

• cites [41] Luo, 2013, Chronic resistance training activates autophagy and reduces apoptosis of muscle cells by modulating IGF-1 and its receptors, Akt/mTOR and Akt/FOXO3a signaling in aged rats, Exp. Gerontol. sourceNot checked yet

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Mito-TEMPO prevents unloading-induced mitochondrial dysfunction and preserves fatigue resistance in rat soleus muscle.

“treatment with the mitochondrial ROS scavenger mito-TEMPO prevents unloading-induced mitochondrial dysfunction and helps preserve fatigue resistance in the soleus muscle in rats [33].”

• cites [33] Sidorenko, 2024, Antioxidant mito-TEMPO prevents the increase in tropomyosin oxidation and mitochondrial calcium accumulation under 7-day rat hindlimb suspension, Free Radic. Biol. Med. sourceNot checked yet

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PGC-1α, regulated by exercise training, is a pivotal transcriptional regulator in mitochondrial biogenesis, impacting muscle morphology and physiological function.

“PGC-1α, regulated by exercise training, serves as a pivotal transcriptional regulator in mitochondrial biogenesis, impacting muscle morphology and physiological function [48,49].”

• cites [48] Lira, 2010, PGC-1alpha regulation by exercise training and its influences on muscle function and insulin sensitivity, Am. J. Physiol. Endocrinol. Metab. sourceNot checked yet

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• cites [49] Ji, 2015, Role of PGC-1α in sarcopenia: Etiology and potential intervention—A mini-review, Gerontology sourceNot checked yet

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Mitochondria play a role in cell signaling, Ca2+ homeostasis, and cell death.

“Mitochondria have not only been considered energy suppliers but have also been closely studied in sarcopenia, observed to play a role in cell signaling, Ca2+ homeostasis, and cell death [28].”

• cites [28] Leduc-Gaudet, J.P., Hussain, S.N.A., Barreiro, E., and Gouspillou, G. (2021). Mitochondrial Dynamics and Mitophagy in Skeletal Muscle Health and Aging. Int. J. Mol. Sci., 22. sourceNot checked yet

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Excessive mutations in ROS-producing mtDNA result in mitochondrial abnormalities, influencing mitophagy, mitochondrial biogenesis, and dynamics, and inducing sarcopenia and alleviated physical activity or exercise training.

“Excessive mutations in ROS-producing mtDNA result in mitochondrial abnormalities, influencing aspects such as mitophagy, mitochondrial biogenesis, and dynamics, and inducing sarcopenia and alleviated physical activity or exercise training [32].”

• cites [32] Amorim, 2022, Mitochondrial and metabolic dysfunction in ageing and age-related diseases, Nat. Rev. Endocrinol. sourceNot checked yet

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Endogenous ROS production by mitochondria triggers oxidative stress, causing mtDNA mutations and damage to mitochondrial membrane proteins.

“The production of endogenous reactive oxygen species (ROS) by mitochondria has traditionally been accepted as an uncontrolled process that triggers oxidative stress, causing large numbers of mtDNA mutations and damage to mitochondrial membrane proteins [29].”

• cites [29] Kujoth, 2005, Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging, Science sourceNot checked yet

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High-intensity interval training in mice improved grip strength, treadmill endurance, and gait speed, and increased muscle mass, muscle fiber size, and mitochondrial biomass.

“those undergoing 10-min uphill treadmill, high-intensity interval training (HIIT) sessions over 16 weeks showed significant improvements in grip strength, treadmill endurance, and gait speed, and exhibited increased muscle mass, larger muscle fiber size, and greater mitochondrial biomass [19].”

• cites [19] Seldeen, 2018, High Intensity Interval Training Improves Physical Performance and Frailty in Aged Mice, J. Gerontol. Ser. A Biol. Sci. Med. Sci. sourceNot checked yet

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Etanercept prevents muscle atrophy and extends lifespan in aged mice through preservation of muscle fiber cross-sectional area and type II muscle fibers.

“etanercept, a TNF-α inhibitor, has demonstrated efficacy in preventing muscle atrophy and extending lifespan in aged mice through mechanisms including the preservation of muscle fiber cross-sectional area and type II muscle fibers [27].”

• cites [27] Sciorati, 2020, Pharmacological blockade of TNFα prevents sarcopenia and prolongs survival in aging mice, Aging sourceNot checked yet

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All three types of exercise (resistance, aerobic, and high-intensity interval work) are effective in managing sarcopenia.

“A review of the extant literature indicates that all three types of exercise are effective in managing sarcopenia.”

• AssumptionRests on an assumption: Findings from rodent exercise studies are applicable to human sarcopenia.

May combine two claims.

MOTS-c administration enhances muscle glucose uptake, boosts exercise endurance, and prevents muscle atrophy by directly binding and activating casein kinase 2.

“MOTS-c administration enhances muscle glucose uptake, boosts exercise endurance, and prevents muscle atrophy by directly binding and activating casein kinase 2 (CK2) [25].”

• cites [25] Kumagai, 2024, MOTS-c modulates skeletal muscle function by directly binding and activating CK2, iScience sourceNot checked yet

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Loss of Parkin results in reduced muscle strength, impaired mitochondrial respiration, and increased sensitivity of skeletal muscle to mPTP opening in mice.

“Loss of Parkin, a mitophagy protein, results in reduced muscle strength, impaired mitochondrial respiratory, and an increased sensitivity of skeletal muscle to mitochondrial permeability transition pore (mPTP) opening in mice [36].”

• cites [36] Gouspillou, 2018, Protective role of Parkin in skeletal muscle contractile and mitochondrial function, J. Physiol. sourceNot checked yet

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Overexpression of PGC-1α increases mitochondrial protein content and antioxidant enzyme activity, modifies gene expression, attenuating the impact of aging on muscle tissue.

“Overexpression of PGC-1α increases mitochondrial protein content and antioxidant enzyme activity, in addition to modifying gene expression, thereby attenuating the impact of aging on muscle tissue [50,51].”

• cites [50] Garcia, 2018, Overexpression of PGC-1α in aging muscle enhances a subset of young-like molecular patterns, Aging Cell sourceNot checked yet

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• cites [51] Yeo, 2019, Intensified mitophagy in skeletal muscle with aging is downregulated by PGC-1alpha overexpression in vivo, Free Radic. Biol. Med. sourceNot checked yet

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Parkin overexpression reduces aging-related increases in markers of oxidative stress, fibrosis, and apoptosis, enhances mitochondrial content and enzymatic activities, mitigating sarcopenia and improving skeletal muscle performance.

“Parkin overexpression not only reduces aging-related increases in markers of oxidative stress, fibrosis, and apoptosis, but also enhances mitochondrial content and enzymatic activities, mitigating sarcopenia and improving skeletal muscle performance [37].”

• cites [37] Reynaud, 2019, Parkin overexpression protects from ageing-related loss of muscle mass and strength, J. Physiol. sourceNot checked yet

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The enhanced mitophagy after acute exercise is at least partially coordinated by PGC-1α, as the results were not replicated in PGC-1α knockout mice.

“This outcome is at least partially coordinated by PGC-1α, as the results were not replicated in PGC-1α knockout (KO) mice.”

• cites [43] Vainshtein, 2015, Role of PGC-1α during acute exercise-induced autophagy and mitophagy in skeletal muscle, Am. J. Physiol. Cell Physiol. sourceNot checked yet

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After 5 weeks of swimming training, mice exhibited increased basal mitophagy in vivo, indicated by a higher LC3-II/LC3-I ratio and elevated BNIP3 in the mitochondrial fraction, contributing to skeletal muscle adaptation and enhanced muscle strength.

“after 5 weeks of swimming training, mice exhibited increased levels of basal mitophagy in vivo, as indicated by a higher LC3-II/LC3-I ratio and elevated BNIP3 levels in the mitochondrial fraction, thereby contributing to skeletal muscle adaptation and enhanced muscle strength [45].”

• cites [45] Dun, 2017, Exercise Combined with Rhodiola sacra Supplementation Improves Exercise Capacity and Ameliorates Exhaustive Exercise-Induced Muscle Damage through Enhancement of Mitochondrial Quality Control, Oxid. Med. Cell. Longev. sourceNot checked yet

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Lifelong mixed-modality endurance exercise training may help reduce DNA methylation in promoter regions of glycolysis, glycogen synthesis, and TCA-related genes in aged human skeletal muscle, maintaining muscle mass and increasing metabolic capacity.

“lifelong mixed-modality endurance exercise training may help reduce DNA methylation in the promoter regions of glycolysis, glycogen synthesis, and TCA-related genes in aged human skeletal muscle, thereby maintaining muscle mass and increasing metabolic capacity [70].”

• cites [70] Sailani, M.R., Halling, J.F., Møller, H.D., Lee, H., Plomgaard, P., Pilegaard, H., Snyder, M.P., and Regenberg, B. (2019). Lifelong physical activity is associated with promoter hypomethylation of genes involved in metabolism, myogenesis, contractile properties and oxidative stress resistance in aged human skeletal muscle. Sci. Rep., 9. sourceNot checked yet

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In rat skeletal muscle, there was no change in mitochondrial protein levels involved in fission or fusion over 24 h after acute resistance exercise, while four weeks of electrical stimulation-induced resistance training increased Mfn1, Mfn2, and Opa1 protein levels.

“In rat skeletal muscle, there was no change in mitochondrial protein levels involved in mitochondrial fission or fusion over the 24 h after acute resistance exercise, while four weeks of electrical stimulation-induced resistance training (every other day, 12 sessions) increased Mfn1, Mfn2, and Opa1 protein levels [63].”

• cites [63] Kitaoka, 2015, Effect of electrical stimulation-induced resistance exercise on mitochondrial fission and fusion proteins in rat skeletal muscle, Appl. Physiol. Nutr. Metab. sourceNot checked yet

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Under physical activity or exercise training, muscle continuously produces lactate and releases it into the bloodstream, where it is taken up by the liver and used in gluconeogenesis to produce glucose, which participates in the tricarboxylic acid cycle.

“Under physical activity or exercise training, muscle continuously produces lactate and releases it into the bloodstream, and it is subsequently taken up by the liver and used in gluconeogenesis to produce glucose, which participates in the tricarboxylic acid cycle (TCA).”

May combine two claims.

Training volume influences changes in mitochondrial content, whereas relative exercise intensity determines alterations in mitochondrial respiratory function.

“Training volume plays a crucial role in influencing changes in mitochondrial content, whereas relative exercise intensity is a key factor in determining alterations in mitochondrial respiratory function [68].”

• cites [68] Granata, 2018, Training-Induced Changes in Mitochondrial Content and Respiratory Function in Human Skeletal Muscle, Sports Med. sourceNot checked yet

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Twelve-week aerobic exercise mitigates aging-associated decline in PGC-1α and TFAM in aged rats, resulting in expression levels higher than untrained young rats.

“12-week aerobic exercise (treadmill running, 17.5 m/min for 45 min/day) could mitigate the aging-associated decline in PGC-1α and mitochondrial transcription factor A (TFAM) in aged rats, resulting in expression levels that are even higher than those observed in untrained young rats [55].”

• cites [55] Kang, 2013, Exercise training attenuates aging-associated mitochondrial dysfunction in rat skeletal muscle: Role of PGC-1α, Exp. Gerontol. sourceNot checked yet

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Opa1 deficiency reduces muscle fiber size, causes mitochondrial dysfunction and mtDNA release, enhances FGF21, characterized by NF-κB activation, contributing to muscle loss and weakness.

“Opa1 deficiency reduces muscle fiber size, causes mitochondrial dysfunction and mitochondrial DNA release, and enhances FGF21, characterized by NF-κB activation, which contributes to muscle loss and weakness [61].”

• cites [61] Noguera, 2018, Mitochondrial DNA and TLR9 drive muscle inflammation upon Opa1 deficiency, EMBO J. sourceNot checked yet

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Eight weeks of treadmill training in mice enhances PPARδ activity, which activates the Lin28a/miRNA let-7b-5p pathway in skeletal muscle, leading to changes in mitochondrial metabolism in a PGC-1α-dependent manner.

“just eight weeks of treadmill training in mice enhances the activity of peroxisome proliferator-activated receptor delta (PPARδ), which in turn activated the Lin28a/miRNA let-7b-5p pathway in the skeletal muscle, leading to changes in mitochondrial metabolism in a PGC-1α-dependent manner [54].”

• cites [54] Araujo, 2020, Regulation of Lin28a-miRNA let-7b-5p pathway in skeletal muscle cells by peroxisome proliferator-activated receptor delta, Am. J. Physiol. Cell Physiol. sourceNot checked yet

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Previous studies reported diminished expressions of mitochondrial respiratory complex subunits, mitochondrial respiration, and ATP levels in skeletal muscle.

“Previous studies have reported diminished expressions of mitochondrial respiratory complex subunits, mitochondrial respiration, and ATP levels in skeletal muscle [66].”

• cites [66] Bratic, 2013, The role of mitochondria in aging, J. Clin. Investig. sourceNot checked yet

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Mitochondria-related proteins Drp1, Mfn2, PGC-1α, and COX significantly increased in mice through Sestrin2 in an AMPKα2-dependent manner following 8-month treadmill training, suggesting aerobic exercise enhanced mitochondrial fusion and fission in gastrocnemius with age-related sarcopenia.

“The mitochondria-related proteins Drp1, Mfn2, PGC-1α, and COX significantly increased in mice through Sestrin2 in an AMP-activated protein kinase α2 (AMPKα2)-dependent manner following an 8-month treadmill training (60 min/day, 12 m/min) program, suggesting that aerobic exercise enhanced the mitochondrial fusion and fission in gastrocnemius with age-related sarcopenia [62].”

• cites [62] Liu, 2021, Aerobic Exercise Improves Mitochondrial Function in Sarcopenia Mice Through Sestrin2 in an AMPKα2-Dependent Manner, J. Gerontol. Ser. A Biol. Sci. Med. Sci. sourceNot checked yet

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HIIT over 6 weeks improved muscle mitochondrial respiration, prompting substantial ATP regeneration by mitochondrial OXPHOS in young human skeletal muscle tissue.

“HIIT over 6 weeks improved muscle mitochondrial respiration, prompting substantial ATP regeneration by mitochondrial OXPHOS in young human skeletal muscle tissue [69].”

• cites [69] Granata, 2021, High-intensity training induces non-stoichiometric changes in the mitochondrial proteome of human skeletal muscle without reorganisation of respiratory chain content, Nat. Commun. sourceNot checked yet

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Aging leads to increased occurrence of mitochondrial fission, aligning with fragmented mitochondrial structures commonly observed in skeletal muscle of aged rodents.

“Several studies have demonstrated that aging leads to an increased occurrence of mitochondrial fission, which aligns with the fragmented mitochondrial structures commonly observed in the skeletal muscle of aged rodents [58].”

• cites [58] Joseph, 2012, The impact of aging on mitochondrial function and biogenesis pathways in skeletal muscle of sedentary high- and low-functioning elderly individuals, Aging Cell sourceNot checked yet

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Regular exercise serves as a non-invasive therapeutic approach and highly effective intervention for metabolic syndrome linked to sarcopenia.

“A growing body of evidence highlights that regular exercise serves as a non-invasive therapeutic approach and a highly effective intervention for addressing metabolic syndrome linked to sarcopenia [16].”

• cites [16] Shen, 2023, Exercise for sarcopenia in older people: A systematic review and network meta-analysis, J. Cachexia Sarcopenia Muscle sourceNot checked yet

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• AssumptionRests on an assumption: Findings from rodent exercise studies are applicable to human sarcopenia.

May combine two claims.

Exercise triggers release of exerkines, which contribute to increased muscle anabolism, bone formation, mitochondrial function, glucose utilization, and fatty acid oxidation, ultimately alleviating sarcopenia.

“exercise triggers the release of bioactive factors known as exerkines, which contribute to increased muscle anabolism, bone formation, mitochondrial function, glucose utilization, and fatty acid oxidation (FAO), ultimately alleviating sarcopenia [72].”

• cites [72] Kirk, 2020, Muscle, Bone, and Fat Crosstalk: The Biological Role of Myokines, Osteokines, and Adipokines, Curr. Osteoporos. Rep. sourceNot checked yet

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• AssumptionRests on an assumption: Findings from rodent exercise studies are applicable to human sarcopenia.

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

Muscle activity during exercise requires substantial energy from various metabolic pathways, greatly relying on mitochondrial redox biology.

“Muscle activity during exercise requires substantial energy from various metabolic pathways, which thus greatly relies on mitochondrial redox biology.”

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The reaction to exercise is intended to rectify dysregulated mitochondrial dynamics and preserve muscle health.

“The reaction is intended to rectify dysregulated mitochondrial dynamics and preserve muscle health.”

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Restoring mitochondrial dynamics to an appropriate range in atrophic skeletal muscle promotes muscle health and slows progression of sarcopenia.

“Therefore, it is imperative to restore mitochondrial dynamics to an appropriate range in atrophic skeletal muscle in order to promote muscle health and slow the progression of sarcopenia.”

• AssumptionRests on an assumption: Findings from rodent exercise studies are applicable to human sarcopenia.

May combine two claims.

Primary aging causes defects in mitochondrial energetics and loss of muscle mass, along with decreased physical activity and exercise.

“In skeletal muscle, primary aging causes defects in mitochondrial energetics and a loss of muscle mass, along with decreased physical activity and exercise [65].”

• cites [65] Cartee, 2016, Exercise Promotes Healthy Aging of Skeletal Muscle, Cell Metab. sourceNot checked yet

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Opa1 levels decline with age in sedentary but not active adults, associated with muscle mass, inflammation, and metabolic homeostasis in muscle.

“Opa1 levels decline with age in sedentary but not active adults, which is associated with muscle mass, inflammation, and metabolic homeostasis in muscle [59].”

• cites [59] Tezze, 2017, Age-Associated Loss of OPA1 in Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation, and Epithelial Senescence, Cell Metab. sourceNot checked yet

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White adipose tissue functions as an important endocrine organ regulating metabolism through releasing adipokines, in addition to energy storage and adaptive thermogenesis.

“Presently, it is acknowledged that white adipose tissue (WAT) not only has functions in energy storage and adaptive thermogenesis but also serves as an important endocrine organ, regulating metabolism through releasing adipokines [73].”

• cites [73] Goody, 2019, MicroRNAs in brown and beige fat, Biochim. Biophys. Acta Mol. Cell Biol. Lipids sourceNot checked yet

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After H2O2 treatment, skeletal muscle cells lower ATP levels, activate AMPK, and increase PGC-1α mRNA, suggesting H2O2 promotes PGC-1α expression by AMPK, accelerating mitochondrial biogenesis.

“after H2O2 treatment, skeletal muscle cells can lower ATP levels, activate AMPK, and increase PGC-1α mRNA, suggesting that H2O2 can promote PGC-1α expression by AMPK, finally accelerating mitochondrial biogenesis [53].”

• cites [53] Irrcher, 2009, Interactions between ROS and AMP kinase activity in the regulation of PGC-1alpha transcription in skeletal muscle cells, Am. J. Physiol. Cell Physiol. sourceNot checked yet

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Regular exercise contributes to reduced age-related oxidative damage, enhanced autophagy, improved mitochondrial function, myokine profiles, IGF-1 signaling pathways, and insulin sensitivity.

“Consistent research findings highlight the significant health benefits of regular exercise, contributing to reduced age-related oxidative damage, enhanced autophagy, and improved mitochondrial function, myokine profiles, IGF-1 signaling pathways, and insulin sensitivity [96].”

• cites [96] Angulo, J., El Assar, M., Álvarez-Bustos, A., and Rodríguez-Mañas, L. (2020). Physical activity and exercise: Strategies to manage frailty. Redox Biol., 35. sourceNot checked yet

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Myostatin is a powerful inhibitor of muscle mass growth and development that acts via Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and reducing myotube size.

“Myostatin is a powerful inhibitor of muscle mass growth and development that acts via Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and reducing myotube size [111].”

• cites [111] Trendelenburg, 2009, Myostatin reduces Akt/TORC1/p70S6K signaling, inhibiting myoblast differentiation and myotube size, Am. J. Physiol. Cell Physiol. sourceNot checked yet

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Acute exhaustive treadmill exercise triggered increased mitochondrial respiration and mitochondrial biogenesis in mice, suggesting beneficial adaptations of physical exercise may be driven by interaction between IL-6 and REVERBα.

“An acute exhaustive treadmill exercise (20 m/min for 90 min) triggered increased mitochondrial respiration and mitochondrial biogenesis in mice, suggesting that the beneficial adaptations of physical exercise, such as enhanced mitochondrial content and improved autophagy, may be driven by the interaction between IL-6 and REVERBα [91] (Table 1).”

• cites [91] Pinto, A.P., Muñoz, V.R., da Rocha, A.L., Rovina, R.L., Ferrari, G.D., Alberici, L.C., Simabuco, F.M., Teixeira, G.R., Pauli, J.R., and de Moura, L.P. (2022). IL-6 deletion decreased REV-ERBα protein and influenced autophagy and mitochondrial markers in the skeletal muscle after acute exercise. Front. Immunol., 13. sourceNot checked yet

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Exercise-induced adiponectin reduces white fat synthesis to mitigate muscle atrophy, with mechanisms including enhanced insulin sensitivity, improved glucose uptake, promotion of myogenesis, inhibition of muscle protein degradation, and increased muscle hypertrophy.

“Exercise-induced adiponectin also reduces white fat synthesis to mitigate muscle atrophy, with the primary mechanisms underlying this effect including enhanced insulin sensitivity, improved glucose uptake, promotion of myogenesis, inhibition of muscle protein degradation, and increased muscle hypertrophy [87,88].”

• cites [87] Abou-Samra, M., Selvais, C.M., Dubuisson, N., and Brichard, S.M. (2020). Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together?. Int. J. Mol. Sci., 21. sourceNot checked yet

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• cites [88] Alizadeh Pahlavani, H. (2022). Exercise Therapy for People With Sarcopenic Obesity: Myokines and Adipokines as Effective Actors. Front. Endocrinol., 13. sourceNot checked yet

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Circulating IL-6 concentrations increase dramatically in response to exercise and are intricately tied to exercise intensity, meaning IL-6 is released from skeletal muscle to restore muscle function following exercise.

“Circulating IL-6 concentrations increase dramatically in response to exercise and are intricately tied to exercise intensity, meaning that IL-6 is released from the skeletal muscle to restore muscle function following exercise [110].”

• cites [110] Kistner, 2022, Interleukin 6 as an energy allocator in muscle tissue, Nat. Metab. sourceNot checked yet

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Intensive lifestyle interventions lasting 12 weeks (three times a week), including whey supplementation and resistance exercise, can significantly lower leptin level, restore metabolic hormone levels, and ameliorate muscle mass in sarcopenic patients.

“Intensive lifestyle interventions lasting 12 weeks (three times a week), including whey supplementation and resistance exercise, can significantly lower the leptin level, restore metabolic hormone levels, and ameliorate muscle mass in sarcopenic patients [85].”

• cites [85] Li, 2019, Circulating factors associated with sarcopenia during ageing and after intensive lifestyle intervention, J. Cachexia Sarcopenia Muscle sourceNot checked yet

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In early aging mice, aerobic exercise, resistance exercise, whole-body vibration, and electrical stimulation over 4 weeks inhibited oxidative stress and apoptosis and enhanced skeletal muscle mass and function by activating the IGF-1/IGF-1R-PI3K/Akt signaling pathway.

“One study result demonstrated that aerobic exercise (12 m/min for 60 min daily), resistance exercise (60 min daily), whole-body vibration (15 min daily), and electrical stimulation (15 min daily) over 4 weeks inhibited oxidative stress and apoptosis and enhance skeletal muscle mass and function in mice undergoing early aging by activating the IGF-1/IGF-1R–PI3K/Akt signaling pathway [90] (Table 1).”

• cites [90] Li, B., Feng, L., Wu, X., Cai, M., Yu, J.J., and Tian, Z. (2022). Effects of different modes of exercise on skeletal muscle mass and function and IGF-1 signaling during early aging in mice. J. Exp. Biol., 225. sourceNot checked yet

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Exercise-induced adipokines are vital in reducing inflammation, promoting mitochondrial biogenesis, and decreasing white fat synthesis to attenuate sarcopenia.

“Therefore, according to the above studies, exercise-induced adipokines are vital in reducing inflammation, promoting mitochondrial biogenesis, and decreasing white fat synthesis to attenuate sarcopenia.”

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Disruption of these signaling pathways in muscle with muscle-specific BDNF knockout leads to reduced ATP production through FAO and diminished amino acid release from fasting-induced autophagy, resulting in myofiber necrosis.

“Since these signaling pathways are also critical for mitochondrial biogenesis and autophagy during fasting, their disruption in muscle with muscle-specific BDNF knockout leads to a reduction in ATP production through FAO, as well as diminished amino acid release from fasting-induced autophagy, resulting in myofiber necrosis [109].”

• cites [109] Yang, 2019, Muscle-generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility, Sci. Signal. sourceNot checked yet

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Myostatin is increased in patients with muscle loss, and its deficiency increases muscle cell protein synthesis, reduces degradation, promotes mitochondrial biogenesis, and preserves muscle function.

“Myostatin is increased in patients with muscle loss, and its deficiency increases muscle cell protein synthesis, reduces degradation, promotes mitochondrial biogenesis, and preserves muscle function [100].”

• cites [100] Rodgers, 2022, Myostatin/Activin Receptor Ligands in Muscle and the Development Status of Attenuating Drugs, Endocr. Rev. sourceNot checked yet

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IGF-1 levels are inhibited in numerous chronic diseases, including sarcopenia, potentially leading to muscle atrophy resulting from altered protein synthesis, ubiquitin-proteasome system activity, autophagy, and impaired muscle regeneration.

“However, IGF-1 levels are inhibited in numerous chronic diseases, including sarcopenia, potentially leading to muscle atrophy resulting from the combined impacts of altered protein synthesis, ubiquitin-proteasome system (UPS) activity, autophagy, and impaired muscle regeneration [107].”

• cites [107] Ahmad, S.S., Ahmad, K., Lee, E.J., Lee, Y.H., and Choi, I. (2020). Implications of Insulin-Like Growth Factor-1 in Skeletal Muscle and Various Diseases. Cells, 9. sourceNot checked yet

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Deposition of intracellular lipids leads to mitochondrial dysfunction and increased ROS production in muscle, disrupts muscle protein synthesis, impairs skeletal muscle function, and causes sarcopenia.

“Recently, great importance has been attached to the deposition of intracellular lipids, which leads to further mitochondrial dysfunction and increased ROS production in muscle, disrupts muscle protein synthesis, and impairs skeletal muscle function, causing the development of sarcopenia [82].”

• cites [82] Lipina, 2017, Lipid modulation of skeletal muscle mass and function, J. Cachexia Sarcopenia Muscle sourceNot checked yet

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IGF-1 controls skeletal muscle anabolism and catabolism, exerting anabolic effects by regulating mitochondrial function, ROS detoxification, and the basal inflammatory state in aging individuals.

“IGF-1, a key factor controlling skeletal muscle anabolism and catabolism, exerts its anabolic effects on skeletal muscle by regulating mitochondrial function, ROS detoxification, and the basal inflammatory state in aging individuals [106].”

• cites [106] Ascenzi, 2019, Effects of IGF-1 isoforms on muscle growth and sarcopenia, Aging Cell sourceNot checked yet

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TGF-β2, an exercise-induced adipokine, is stimulated by exercise-induced lactate, enhancing glucose uptake in skeletal muscle and boosting mitochondrial function.

“Transforming growth factor-beta 2 (TGF-β2), an exercise-induced adipokine, is stimulated by exercise-induced lactate, enhancing glucose uptake in skeletal muscle and boosting mitochondrial function, shedding light on adipose–muscle tissue crosstalk [79] (Table 1).”

• cites [79] Takahashi, 2019, TGF-β2 is an exercise-induced adipokine that regulates glucose and fatty acid metabolism, Nat. Metab. sourceNot checked yet

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AdipoR1-deficient mice show reduced PGC-1α expression, mitochondrial biogenesis and function, and endurance training capacity.

“AdipoR1-deficient mice show reduced PGC-1α expression, mitochondrial biogenesis and function, and endurance training capacity [87].”

• cites [87] Abou-Samra, M., Selvais, C.M., Dubuisson, N., and Brichard, S.M. (2020). Adiponectin and Its Mimics on Skeletal Muscle: Insulin Sensitizers, Fat Burners, Exercise Mimickers, Muscling Pills … or Everything Together?. Int. J. Mol. Sci., 21. sourceNot checked yet

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Exercise and cold exposure enhance generation and secretion of irisin from skeletal muscle, thereby inducing myogenesis, preventing muscle atrophy, improving energy metabolism, enhancing cellular homeostasis, and promoting mitochondrial quality control.

“The stimulation of exercise and cold exposure enhance the generation and secretion of irisin from skeletal muscle, thereby inducing myogenesis, preventing muscle atrophy, improving energy metabolism, enhancing cellular homeostasis, and promoting mitochondrial quality control [98].”

• cites [98] Zhang, 2022, Irisin, an exercise-induced bioactive peptide beneficial for health promotion during aging process, Ageing Res. Rev. sourceNot checked yet

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Adiponectin contributes to activation of brown adipose tissue and promotes thermogenesis, further supporting preservation of muscle mass and overall metabolic health.

“Additionally, adiponectin contributes to the activation of brown adipose tissue (BAT) and promotes thermogenesis, further supporting the preservation of muscle mass and overall metabolic health [89].”

• cites [89] Sarjeant, K., and Stephens, J.M. (2012). Adipogenesis. Cold Spring Harb. Perspect. Biol., 4. sourceNot checked yet

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The ensuing inflammation contributes to insulin resistance, exacerbated by muscle catabolism, leading to increased fat accumulation and muscle loss.

“The ensuing inflammation further contributes to insulin resistance, exacerbated by muscle catabolism, thereby leading to increased fat accumulation and muscle loss [83,84].”

• cites [83] Batsis, 2018, Sarcopenic obesity in older adults: Aetiology, epidemiology and treatment strategies, Nat. Rev. Endocrinol. sourceNot checked yet

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• cites [84] Schrager, 2007, Sarcopenic obesity and inflammation in the InCHIANTI study, J. Appl. Physiol. sourceNot checked yet

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Resistance exercise for 12 weeks elevated irisin levels and improved muscle strength in mice and older adults, which might present an effective strategy to counteract age-related decline in muscle function.

“Resistance exercise for 12 weeks (ladder climbing exercise three times a week in mice; elastic band exercise program consisting of 1 h sessions twice a week for older adults) elevated irisin levels and improved muscle strength, which might present an effective strategy to counteract age-related decline in muscle function [92] (Table 1).”

• cites [92] Kim, 2015, Resistance exercise training increases the expression of irisin concomitant with improvement of muscle function in aging mice and humans, Exp. Gerontol. sourceNot checked yet

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A 4-month endurance training program in mice enhanced AdipoR1 gene expression, circulating adiponectin levels, AMPK/PGC-1α-related mitochondrial biogenesis, and Akt/mTOR-mediated protein synthesis and proliferation, showing positive effects on sarcopenia development and muscle health.

“A 4-month endurance training (45 min/time, 3 times/week) program in mice enhanced AdipoR1 gene expression, circulating adiponectin levels, AMPK/PGC-1α-related mitochondrial biogenesis, and Akt/mTOR-mediated protein synthesis and proliferation, showcasing positive effects on sarcopenia development and muscle health [74] (Table 1).”

• cites [74] Inoue, 2017, Exercise restores muscle stem cell mobilization, regenerative capacity and muscle metabolic alterations via adiponectin/AdipoR1 activation in SAMP10 mice, J. Cachexia Sarcopenia Muscle sourceNot checked yet

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Obesity gives rise to a state of mild inflammation marked by secretion of leptin, which elevates pro-inflammatory cytokines and results in a diminished anabolic response to IGF-1.

“It is worth noting that obesity gives rise to a state of mild inflammation, marked by the secretion of leptin, which elevates the levels of pro-inflammatory cytokines, resulting in a diminished anabolic response to IGF-1.”

• cites [83] Batsis, 2018, Sarcopenic obesity in older adults: Aetiology, epidemiology and treatment strategies, Nat. Rev. Endocrinol. sourceNot checked yet

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• cites [84] Schrager, 2007, Sarcopenic obesity and inflammation in the InCHIANTI study, J. Appl. Physiol. sourceNot checked yet

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In mice, leptin deficiency promotes fatty acid β-oxidation, enhancing mitochondrial protection against ROS through HK-II regulation, acting on mitochondrial function and quality control mechanisms.

“Studies in mice show that leptin deficiency promotes fatty acid β-oxidation, enhancing mitochondrial protection against ROS through HK-II regulation, acting on mitochondrial function and quality control mechanisms [76].”

• cites [76] Potes, Y., Díaz-Luis, A., Bermejo-Millo, J.C., Pérez-Martínez, Z., de Luxán-Delgado, B., Rubio-González, A., Menéndez-Valle, I., Gutiérrez-Rodríguez, J., Solano, J.J., and Caballero, B. (2023). Melatonin Alleviates the Impairment of Muscle Bioenergetics and Protein Quality Control Systems in Leptin-Deficiency-Induced Obesity. Antioxidants, 12. sourceNot checked yet

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Osteokines are essential for regulating the expression of PGC-1α, improving insulin sensitivity, and promoting mitochondria biogenesis in skeletal muscle.

“Osteokines are essential for regulating the expression of PGC-1α, improving insulin sensitivity, and promoting mitochondria biogenesis in skeletal muscle [134].”

• cites [134] Mera, 2018, Regulation of Energy Metabolism by Bone-Derived Hormones, Cold Spring Harb. Perspect. Med. sourceNot checked yet

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Osteocalcin, mainly synthesized and released by osteoblasts, is involved in increasing muscular mitochondria, inhibiting myoblast proliferation and bone formation, and regulating energy homeostasis, and is known to increase during 8-week treadmill running in obese young males.

“Osteocalcin, mainly synthesized and released by osteoblasts, is involved in increasing muscular mitochondria, inhibiting myoblast proliferation and bone formation, and regulating energy homeostasis, known to increase during 8-week treadmill running (65–75% VO2max per session, four sessions per week) in obese young males [137].”

• cites [137] Kim, 2015, The effects of aerobic exercise training on serum osteocalcin, adipocytokines and insulin resistance on obese young males, Clin. Endocrinol. sourceNot checked yet

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In older mice, osteocalcin signaling in myotubes promotes protein synthesis without affecting protein breakdown via activation of the mTOR pathway, and osteocalcin is necessary and sufficient to attenuate age-related muscle loss.

“In older mice, osteocalcin signaling in the myotubes promotes protein synthesis without affecting protein breakdown via activation of the mTOR pathway, uncovering that osteocalcin is both necessary and sufficient to attenuate age-related muscle loss [129].”

• cites [129] Mera, 2016, Osteocalcin is necessary and sufficient to maintain muscle mass in older mice, Mol. Metab. sourceNot checked yet

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Exercise can induce significant adaptations in skeletal muscle, including increased muscle mass, enhanced muscle regeneration and hypertrophy, reduced ROS, elevated release of hormones, and improved mitochondrial function.

“Exercise can induce significant adaptations in skeletal muscle, including increased muscle mass, enhanced muscle regeneration and hypertrophy, reduced ROS, elevated the release of hormones, and improved mitochondrial function.”

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Following exercise training on a treadmill, SeP-deficient mice exhibited increased aerobic exercise capacity accompanied by increased mitochondrial biogenesis and function in skeletal muscle, associated with increased ROS, AMPK activation, and increased PGC-1α activity.

“Following exercise training on a treadmill (30 min per day for 4 weeks), SeP-deficient mice exhibited an increased aerobic exercise capacity accompanied by increased mitochondrial biogenesis and function in skeletal muscle, an effect associated with increased ROS, AMPK activation, and increased PGC-1α activity [93] (Table 1).”

• cites [93] Misu, 2017, Deficiency of the hepatokine selenoprotein P increases responsiveness to exercise in mice through upregulation of reactive oxygen species and AMP-activated protein kinase in muscle, Nat. Med. sourceNot checked yet

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Osteokines are novel exercise-inducible soluble factors secreted by osteocytes, osteoblasts, and osteoclasts that play an important role in the body's response to exercise, mainly including RANKL, sclerostin, osteocalcin, FGF23, Wnt3a, TGF-β, IGF-1, and PGE2.

“Osteokines, novel exercise-inducible soluble factors secreted by osteocytes, osteo blasts, and osteoclasts, play an important role in the body’s response to exercise, mainly including RANKL [127], sclerostin [128], osteocalcin [129], fibroblast growth factor 23 (FGF23) [95], Wnt3a [130], TGF-β [131], IGF-1 [132], and prostaglandin E2 (PGE2) [133] (Figure 3).”

• cites [127] Bonnet, 2019, RANKL inhibition improves muscle strength and insulin sensitivity and restores bone mass, J. Clin. Investig. sourceNot checked yet

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• cites [128] Kurgan, 2023, Sclerostin Influences Exercise-Induced Adaptations in Body Composition and White Adipose Tissue Morphology in Male Mice, J. Bone Min. Res. sourceNot checked yet

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• cites [129] Mera, 2016, Osteocalcin is necessary and sufficient to maintain muscle mass in older mice, Mol. Metab. sourceNot checked yet

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An increasing number of exerkines released during exercise present the potential to induce mitophagy, mitochondrial biogenesis, dynamics, autophagy, and redox to enhance mitochondrial homeostasis, thereby maintaining skeletal muscle metabolic balance and mitochondrial health.

“Very importantly, an increasing number of exerkines released during exercise present the potential to induce mitophagy, mitochondrial biogenesis, dynamics, autophagy, and redox to enhance mitochondrial homeostasis, thereby maintaining the skeletal muscle metabolic balance and mitochondrial health.”

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FGF21 is a marker of mitochondrial dysfunction and aging, playing a crucial role in regulating metabolic activity.

“FGF21 is acknowledged as a marker of mitochondrial dysfunction and aging, playing a crucial role in regulating metabolic activity [113].”

• cites [113] Romanello, V. (2020). The Interplay between Mitochondrial Morphology and Myomitokines in Aging Sarcopenia. Int. J. Mol. Sci., 22. sourceNot checked yet

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During exercise, FGF21 is released from muscles into the bloodstream to optimize mitochondria, thus preventing certain diseases, especially sarcopenia.

“During exercise (e.g., resistance training), FGF21 is released from muscles into the bloodstream to optimize mitochondria that act as an energy generator, thus preventing certain diseases, especially sarcopenia [115].”

• cites [115] Sanchis-Gomar, F., Pareja-Galeano, H., Mayero, S., Perez-Quilis, C., and Lucia, A. (2014). New molecular targets and lifestyle interventions to delay aging sarcopenia. Front. Aging Neurosci., 6. sourceNot checked yet

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Fetuin-A induces a pro-inflammatory milieu by polarizing M1 macrophages in WAT, generating ROS and reducing insulin sensitivity, which combined with other pro-inflammatory cytokines causes the development of sarcopenia.

“Fetuin-A, a systemic calcification inhibitor, induces a pro-inflammatory milieu by polarizing M1 macrophages in WAT, generating ROS and reducing insulin sensitivity, which combined with other pro-inflammatory cytokines causes the development of sarcopenia [122,123,124,125].”

• cites [122] Armandi, A., Rosso, C., Caviglia, G.P., Ribaldone, D.G., and Bugianesi, E. (2021). The Impact of Dysmetabolic Sarcopenia Among Insulin Sensitive Tissues: A Narrative Review. Front. Endocrinol., 12. sourceNot checked yet

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• cites [123] Chang, W.T., Wu, C.H., Hsu, L.W., Chen, P.W., Yu, J.R., Chang, C.S., Tsai, W.C., and Liu, P.Y. (2017). Serum vitamin D, intact parathyroid hormone, and Fetuin A concentrations were associated with geriatric sarcopenia and cardiac hypertrophy. Sci. Rep., 7. sourceNot checked yet

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• cites [124] de Oliveira Dos Santos, A.R., de Oliveira Zanuso, B., Miola, V.F.B., Barbalho, S.M., Santos Bueno, P.C., Flato, U.A.P., Detregiachi, C.R.P., Buchaim, D.V., Buchaim, R.L., and Tofano, R.J. (2021). Adipokines, Myokines, and Hepatokines: Crosstalk and Metabolic Repercussions. Int. J. Mol. Sci., 22. sourceNot checked yet

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• cites [125] Wang, 2020, lncRNA DLEU2 acts as a miR-181a sponge to regulate SEPP1 and inhibit skeletal muscle differentiation and regeneration, Aging sourceNot checked yet

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In mice, elevated lactate decreased the number of apoptotic nuclei in aged muscle and restored mitochondrial function through activation of the CREB-PGC-1α pathway, thereby helping to mitigate sarcopenia.

“In mice, elevated lactate decreased the number of apoptotic nuclei in aged muscle and restored mitochondrial function through the activation of the CREB-PGC-1α pathway, thereby helping to mitigate sarcopenia [117].”

• cites [117] Sayed, 2018, The Protective Effect of Melatonin Against Age-Associated, Sarcopenia-Dependent Tubular Aggregate Formation, Lactate Depletion, and Mitochondrial Changes, J. Gerontol. Ser. A Biol. Sci. Med. Sci. sourceNot checked yet

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Exercise training increases MCT1 levels and enhances lactate transport to muscle, whereas MCTs are reduced in aging muscle, thus reducing lactate levels and increasing skeletal muscle fatigue.

“Exercise training increases MCT1 levels and enhances lactate transport to muscle, whereas MCTs are reduced in aging muscle, thus reducing lactate levels and increasing skeletal muscle fatigue [116].”

• cites [116] Masuda, 2009, Evidence for differential regulation of lactate metabolic properties in aged and unloaded rat skeletal muscle, Exp. Gerontol. sourceNot checked yet

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SeP is a hepatokine upregulated in aging that causes signaling resistance via reductive stress, which is involved in physical inactivity-mediated muscle atrophy.

“Of new note, SeP is identified as a hepatokine upregulated in aging, and it causes signaling resistance via reductive stress, which is involved in physical inactivity-mediated muscle atrophy [126].”

• cites [126] Abuduwaili, 2023, Selenoprotein P deficiency protects against immobilization-induced muscle atrophy by suppressing atrophy-related E3 ubiquitin ligases, Am. J. Physiol. Endocrinol. Metab. sourceNot checked yet

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Eight-week concurrent training (resistance and endurance training, three sessions per week) reduced myostatin and improved body composition, muscle mass, and function in sarcopenic elderly men.

“An eight-week concurrent training (resistance and endurance training, three training sessions per week) reduced myostatin and improved body composition, muscle mass, and function in sarcopenic elderly men [112].”

• cites [112] Bagheri, 2020, The effects of concurrent training order on body composition and serum concentrations of follistatin, myostatin and GDF11 in sarcopenic elderly men, Exp. Gerontol. sourceNot checked yet

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RANKL inhibition improves muscle strength and insulin sensitivity in osteoporotic mice and humans through the RANK/RANKL/OPG signaling pathways, potentially representing a new therapeutic avenue for sarcopenia.

“Research has shown that RANKL inhibition improves muscle strength and insulin sensitivity in osteoporotic mice and humans through the RANK/RANKL/OPG signaling pathways, potentially representing a new therapeutic avenue for sarcopenia [127].”

• cites [127] Bonnet, 2019, RANKL inhibition improves muscle strength and insulin sensitivity and restores bone mass, J. Clin. Investig. sourceNot checked yet

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Muscle FGF21 expression is very low in normal healthy muscle but is released under conditions including fasting, exercise, mitochondrial dysfunction, mitochondrial myopathy, and metabolic disorders.

“The expression level of FGF21 is very low in normal healthy muscle. However, muscle FGF21 is released under conditions including fasting, exercise, mitochondrial dysfunction, mitochondrial myopathy, and metabolic disorders [114].”

• cites [114] Keipert, 2014, Skeletal muscle mitochondrial uncoupling drives endocrine cross-talk through the induction of FGF21 as a myokine, Am. J. Physiol. Endocrinol. Metab. sourceNot checked yet

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Exercise-induced myokines from activation of signaling pathways reduce muscle protein degradation, promote protein synthesis and hypertrophy, and maintain mitochondrial homeostasis to prevent sarcopenia.

“Overall, exercise-induced myokines from the activation of signaling pathways reduce muscle protein degradation, promote protein synthesis and hypertrophy, and maintain mitochondrial homeostasis to prevent sarcopenia.”