CoChat
Sign Up
Cited by 54Nutrition and Health in AgingMuscle Physiology and DisordersMitochondrial Function and Pathology

From mitochondria to sarcopenia: role of 17β-estradiol and testosterone

Open access
Tian, Xu, Lou, Shujie, Shi, Rengfei·2023·Frontiers in Endocrinology
DOI 10.3389/fendo.2023.1156583PMC PMC10157222
Open this paper in CoChat — free accountOpen PDF

Abstract

Sarcopenia, characterized by a loss of muscle mass and strength with aging, is prevalent in older adults. Although the exact mechanisms underlying sarcopenia are not fully understood, evidence suggests that the loss of mitochondrial integrity in skeletal myocytes has emerged as a pivotal contributor to the complex etiology of sarcopenia. Mitochondria are the primary source of ATP production and are also involved in generating reactive oxygen species (ROS), regulating ion signals, and initiating apoptosis signals in muscle cells. The accumulation of damaged mitochondria due to age-related impairments in any of the mitochondrial quality control (MQC) processes, such as proteostasis, biogenesis, dynamics, and mitophagy, can contribute to the decline in muscle mass and strength associated with aging. Interestingly, a decrease in sex hormones (e.g., 17β-estradiol and testosterone), which occurs with aging, has also been linked to sarcopenia. Indeed, 17β-estradiol and testosterone targeted mitochondria and exhibited activities in regulating mitochondrial functions. Here, we overview the current literature on the key mechanisms by which mitochondrial dysfunction contribute to the development and progression of sarcopenia and the potential modulatory effects of 17β-estradiol and testosterone on mitochondrial function in this context. The advance in its understanding will facilitate the development of potential therapeutic agents to mitigate and manage sarcopenia.

AI snapshot

Written from the paper’s full text.

TL;DR

This narrative review argues that age-related mitochondrial dysfunction—driven by failures in mitochondrial quality control (proteostasis, biogenesis, dynamics, and mitophagy)—is a central initiator of sarcopenia, and that declining 17β-estradiol and testosterone contribute to this process by co-regulating mitochondrial function in skeletal muscle. The authors propose that the age-related loss of both sex hormones may trigger sarcopenia primarily by impairing mitochondrial function rather than acting as an independent factor.

Key findings

  • Mitochondrial dysfunction is positioned as a pivotal contributor to sarcopenia: excessive mPTP opening releases ROS, Ca²⁺, and cytochrome c into the cytosol, initiating apoptotic cascades in muscle fibers and motor neurons that culminate in muscle atrophy and denervation.
  • All four MQC processes are implicated: reduced PGC-1α, NRF1, and TFAM expression in aged/SAMP8 muscle (biogenesis); altered MFN1/MFN2/OPA1 and DRP1/FIS1 expression and fragmented mitochondria in aged muscle (dynamics); and PINK1/Parkin-dependent mitophagy deficits, with Parkin loss reducing muscle force and Parkin overexpression attenuating age-related muscle loss (mitophagy).
  • Mitochondria show sexual dimorphism: female heart, liver, and brain mitochondria have higher antioxidant capacity and produce less ROS than males; female rat gastrocnemius shows higher mtDNA/nDNA and OXPHOS capacity; female brain and heart mitochondria show lower Ca²⁺ uptake.
  • 17β-estradiol acts via ERα, ERβ, and GPER to upregulate PGC-1 and downstream targets (NRF1, TFAM), enhance respiratory capacity and ATP production, and inhibit mPTP opening; testosterone via AR maintains PGC-1α/TFAM expression and mtDNA copy number, and androgen deficiency increases mitophagy (raised LC3 II/I ratio in castrated male mice).
  • The authors note that approximately 70% of mitochondrial protein turnover occurs through non-autophagic degradation (mitoproteases and UPS), with autophagy accounting for about 30%, citing a Drosophila fibroblast proteomics study.

Methods

  • Narrative review; the authors state they "overview the current literature" on mitochondrial dysfunction in sarcopenia and the modulatory effects of 17β-estradiol and testosterone. No systematic search strategy, inclusion criteria, or formal synthesis method is described.
  • Evidence cited is drawn from animal and cell models (e.g., SAMP8 mice, NRF2 knockout mice, MFN2/OPA1/DRP1/FIS1 mutants, castrated rats and mice, OVX rats, C2C12 myoblasts, Drosophila) and human observational data (e.g., aged skeletal muscle biopsies, the Women's Health Initiative).
  • No primary data, sample size, or statistical analysis is reported; the paper presents two schematic figures (Figure 1 on mitochondrial stress and sarcopenia; Figure 2 on estrogen/testosterone mitochondrial protection).

Limitations

  • Stated by the paper: controversy remains over exogenous 17β-estradiol or testosterone supplementation in aging people due to a shortage of clinical trials demonstrating benefits and adverse effects; the specific mechanism of action of the sex hormones on mitochondria "has not yet been elucidated"; it is still unclear whether mitochondrial-localized ERs and AR can directly regulate mtDNA transcription; the role of AR in mitochondrial localization is poorly understood; and the role of mitochondria in motor neuron aging deficits or death is not well understood.
  • Evident from the text: as a narrative review, it lacks a systematic search protocol and formal quality appraisal of the cited studies, and much of the mechanistic evidence derives from rodent, Drosophila, and cell-culture models rather than human trials, limiting direct clinical translation.

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

Integrity signals

Registry

Crossref · 10.3389/fendo.2023.1156583

Cites

160 of 160 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 119 cited sources checked · 0 supported · 0 flagged

  • Findingcitation

    Reduction of the cytosolic antioxidant CuZn-superoxide dismutase (CuZnSOD) observed in mouse nerves and muscle is consistent with sarcopenic muscle loss.

    “For instance, the reduction of the cytosolic antioxidant CuZn-superoxide dismutase (CuZnSOD) was observed in mouse nerves and muscle, consistent with sarcopenic muscle loss (47).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [47] Sataranatarajan, 2015, Neuron specific reduction in cuznsod is not sufficient to initiate a full sarcopenia phenotype, Redox Biol source

      Not checked in the free run.

  • Findingcitation

    Reduced muscle mass and strength has been reported in mice with deletion of the Lonp1 gene in response to muscle disuse.

    “A reduced muscle mass and strength has been reported in mice with deletion of the Lonp1 gene in response to muscle disuse (56).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [56] Xu, 2022, Disuse-associated loss of the protease Lonp1 in muscle impairs mitochondrial function and causes reduced skeletal muscle mass and strength, Nat Commun source

      Not checked in the free run.

  • Findingcitation

    Overexpression of PGC-1α can mitigate the effects of aging on muscle by increasing mitochondrial protein content and antioxidant enzyme activity and altering gene expression to resemble a youthful transcriptome profile.

    “In contrast, overexpression of PGC-1α can mitigate the effects of aging on muscle by increasing mitochondrial protein content and antioxidant enzyme activity and altering gene expression to resemble a youthful transcriptome profile (79, 80).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [79] Garcia, 2018, Overexpression of pgc-1α in aging muscle enhances a subset of young-like molecular patterns, Aging Cell source

      Not checked in the free run.

    • cites [80] Yeo, 2019, Intensified mitophagy in skeletal muscle with aging is downregulated by pgc-1alpha overexpression in vivo, Free Radical Biol Med source

      Not checked in the free run.

  • Findingcitation

    PGC-1α, a master transcriptional regulator of mitochondrial biogenesis, is reduced at both mRNA and protein levels in aged skeletal muscle.

    “PGC-1α, a master transcriptional regulator of mitochondrial biogenesis, has been shown to be reduced at both mRNA and protein levels in aged skeletal muscle (71, 72).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [71] 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 source

      Not checked in the free run.

    • cites [72] Ling, 2004, Multiple environmental and genetic factors influence skeletal muscle pgc-1alpha and pgc-1beta gene expression in twins, J Clin Invest source

      Not checked in the free run.

  • Findingcitation

    Muscle-specific ablation of DRP1 induces severe muscle wasting and weakness, as well as abnormal morphology, function, and Ca2+ homeostasis in mitochondria.

    “Additionally, muscle-specific ablation of DRP1 induces severe muscle wasting and weakness, as well as abnormal morphology, function, and Ca2+ homeostasis in mitochondria (18).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [18] Favaro, 2019, Drp1-mediated mitochondrial shape controls calcium homeostasis and muscle mass, Nat Commun source

      Not checked in the free run.

  • May combine two claims. 38
  • Classified as probably not a substantial claim. 5

  • May combine two claims.

    Findingcitation

    Mild oxidative stress acts as a cellular signal that increases skeletal muscle strength, while further increases reduce strength and promote muscle fatigue.

    “In deed, the production of mild oxidative stress acts as a cellular signal that increases skeletal muscle strength, while further increases reduce strength and promote muscle fatigue (48).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Kramer, 2015, The measurement of reversible redox dependent post-translational modifications and their regulation of mitochondrial and skeletal muscle function, Front Physiol source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Approximately 70% of mitochondrial protein turnover occurs through non-autophagic degradation processes such as mitoproteases and UPS, while autophagy accounts for about 30% of mitochondrial protein turnover.

    “A recent proteomics-based study of Drosophila fibroblasts found that approximately 70% of mitochondrial protein turnover occurs through non-autophagic degradation processes such as mitoproteases and UPS; Autophagy accounts for about 30% of mitochondrial protein turnover (54).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Vincow, 2019, Autophagy accounts for approximately one-third of mitochondrial protein turnover and is protein selective, Autophagy source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Absence of MFN2 in young muscle causes mitochondrial fragmentation, impairs mitochondrial function, enhances ROS production, and promotes the onset of sarcopenia.

    “The absence of MFN2 in young muscle causes mitochondrial fragmentation, impairs mitochondrial function, enhances ROS production, and promotes the onset of sarcopenia (84).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [84] Sebastián, 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.

  • May combine two claims.

    Findingcitation

    Loss of FIS1 results in impaired mitochondrial function and proteostasis in muscle, decreasing both flight capabilities and lifespan in FIS1 mutant flies.

    “Another recent study revealed that loss of FIS1 results in impaired mitochondrial function and proteostasis in muscle, decreasing both flight capabilities and lifespan in FIS1 mutant flies (89).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [89] Lee, 2021, Loss of Fis1 impairs proteostasis during skeletal muscle aging in drosophila, Aging Cell source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    NRF2 knockout exacerbates frailty and sarcopenia of mice during aging, accompanied by reduced expression levels of PGC-1α, NRF1, and TFAM, as well as a reduction of mitochondrial content in the skeletal muscle.

    “NRF2 knockout exacerbated frailty and sarcopenia of mice during aging, accompanied by the reduced expression levels of PGC-1α, NRF1, and TFAM, as well as a reduction of mitochondrial content in the skeletal muscle (19).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [19] Huang, 2019, Nrf2 deficiency exacerbates frailty and sarcopenia by impairing skeletal muscle mitochondrial biogenesis and dynamics in an age-dependent manner, Exp gerontology source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Fragmented and atypically enlarged mitochondria are often observed in aged skeletal muscle, indicating that mitochondrial dynamics are compromised in advanced age.

    “Fragmented and atypically enlarged mitochondria were often observed in aged skeletal muscle (81, 82), indicating that mitochondrial dynamics are compromised in advanced age.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [81] Iqbal, 2013, Expression of mitochondrial fission and fusion regulatory proteins in skeletal muscle during chronic use and disuse, Muscle Nerve source

      Not checked in the free run.

    • cites [82] Leduc-Gaudet, 2015, Mitochondrial morphology is altered in atrophied skeletal muscle of aged mice, Oncotarget source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Suppression of PARL protein in cultured healthy human myotubes lowers mitochondrial mass and insulin-stimulated glycogen synthesis and increases reactive oxygen species production.

    “Suppression of PARL protein in cultured healthy human myotubes lowered mitochondrial mass and insulin-stimulated glycogen synthesis and increased reactive oxygen species production (60).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [60] Civitarese, 2010, Regulation of skeletal muscle oxidative capacity and insulin signaling by the mitochondrial rhomboid protease parl, Cell Metab source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Down-regulation of ClpP in C2C12 mouse myoblasts results in mitochondrial dysfunction and reduction of cell proliferation.

    “Down-regulation of ClpP in C2C12 mouse myoblasts resulted in mitochondrial dysfunction and reduction of cell proliferation (57).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Deepa, 2016, Down-regulation of the mitochondrial matrix peptidase clpp in muscle cells causes mitochondrial dysfunction and decreases cell proliferation, Free Radical Biol Med source

      Not checked in the free run.

  • May combine two claims.

    Findingcitation

    Mutation of Drosophila m-AAA mitochondrial protease leads to impaired mitochondria function, shortened lifespan, and neuronal and muscular degeneration.

    “Mutation of Drosophila m-AAA mitochondrial protease leaded to impaired mitochondria function, shortened lifespan, and neuronal and muscular degeneration (58).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [58] Pareek, 2018, Loss of the drosophila m-aaa mitochondrial protease paraplegin results in mitochondrial dysfunction, shortened lifespan, and neuronal and muscular degeneration, Cell Death Dis source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Aberrant mitochondrial quality control leads to loss of mitochondrial integrity, which is a major factor in muscle degeneration.

    “Aberrant mitochondrial quality control (MQC) leads to loss of mitochondrial integrity, which is thought to be a major factor in muscle degeneration (20).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [20] Picca, 2018, Update on mitochondria and muscle aging: All wrong roads lead to sarcopenia, Biol Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mitochondria have sex-specific features, and alterations in mitochondrial quality control are associated with changes in sex steroid hormone levels.

    “Notably, mitochondria have sex-specific features, and alterations in mitochondrial quality control are associated with changes in sex steroid hormone levels (23, 24).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [23] Vasconsuelo, 2013, Actions of 17β-estradiol and testosterone in the mitochondria and their implications in aging, Ageing Res Rev source

      Not checked in the free run.

    • cites [24] Ventura-Clapier, 2017, Mitochondria: A central target for sex differences in pathologies, Clin Sci (London Engl 1979) source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    17β-estradiol and testosterone target mitochondria and exhibit activities in regulating mitochondrial functions.

    “Indeed, 17β-estradiol and testosterone targeted mitochondria and exhibited activities in regulating mitochondrial functions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mitochondria perform critical functions beyond energy production to maintain homeostasis and function in skeletal myocytes, including regulation of intracellular Ca2+ homeostasis, modulation of cell proliferation, and integration of apoptotic signaling.

    “Emerging evidence suggested that apart from energy production, mitochondria perform other critical functions to maintain homeostasis and function in the skeletal myocytes, including regulation of intracellular Ca2+ homeostasis, modulation of cell proliferation, and integration of apoptotic signaling (17–19).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Ferri, 2020, Role of age-related mitochondrial dysfunction in sarcopenia, Int J Mol Sci source

      Not checked in the free run.

    • cites [18] Favaro, 2019, Drp1-mediated mitochondrial shape controls calcium homeostasis and muscle mass, Nat Commun source

      Not checked in the free run.

    • cites [19] Huang, 2019, Nrf2 deficiency exacerbates frailty and sarcopenia by impairing skeletal muscle mitochondrial biogenesis and dynamics in an age-dependent manner, Exp gerontology source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Activation of apoptotic signals is accompanied by DNA fragmentation and nuclear apoptosis, which eventually leads to muscle atrophy and denervation.

    “The activation of apoptotic signals is accompanied by DNA fragmentation and subsequent nuclear apoptosis, which eventually leads to muscle atrophy and denervation.”
    Quote in the paperSubstantial claim

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

    Premisenone given

    Mitochondria are the primary source of ATP production and are involved in generating reactive oxygen species, regulating ion signals, and initiating apoptosis signals in muscle cells.

    “Mitochondria are the primary source of ATP production and are also involved in generating reactive oxygen species (ROS), regulating ion signals, and initiating apoptosis signals in muscle cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Loss of proteostasis leads to proteome mislocalisation and aggregation, triggers proteotoxic insults and cell death, which adversely impacts the physiological function of skeletal muscle.

    “Loss of proteostasis leads to proteome mislocalisation and aggregation, triggers proteotoxic insults and cell death, which further adversely impacts the physiological function of skeletal muscle (53).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Cristofani, 2019, The regulation of the small heat shock protein B8 in misfolding protein diseases causing motoneuronal and muscle cell death, Front Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    An increase in Ca2+ concentration induces mPTP opening, which further exacerbates the imbalance of intracellular Ca2+ homeostasis, possibly caused by leaky ryanodine receptors in aged skeletal muscle.

    “An increase in Ca2+ concentration induces mPTP opening, which further exacerbates the imbalance of intracellular Ca2+ homeostasis, possibly caused by leaky ryanodine receptors in aged skeletal muscle (49).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [49] Andersson, 2011, Ryanodine receptor oxidation causes intracellular calcium leak and muscle weakness in aging, Cell Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MFN2 deficiency in muscle during aging reduces autophagy, contributes to the accumulation of damaged mitochondria, and triggers age-related mitochondrial dysfunction.

    “For example, MFN2 deficiency promotes muscle aging, also reduces autophagy, and leads to the accumulation of defective mitochondria (84).”
    • Also stated in: § Mitochondrial autophagy in sarcopenia · plain
      “Alternatively, MFN2 deficiency in muscle during aging reduces autophagy, which contributes to the accumulation of damaged mitochondria and triggers age-related mitochondrial dysfunction (84).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [84] Sebastián, 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.

  • May combine two claims.

    Interpretationreasoning

    Mitochondrial Ca2+ overload results in mitochondrial swelling, with perturbation or rupture of the outer membrane, and release of mitochondrial apoptotic factors into the cytosol.

    “Mitochondrial Ca2+ overload results in mitochondrial swelling, with perturbation or rupture of the outer membrane, and in turn the release of mitochondrial apoptotic factors into the cytosol.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Aging provokes alterations of several key mitophagy regulators, leading to mitophagy deficiency and subsequent accumulation of dysfunctional mitochondria in skeletal muscle.

    “Studies indicate that aging provokes certain alternations of several key mitophagy regulators, leading to mitophagy deficiency and subsequent accumulation of dysfunctional mitochondria in skeletal muscle (91, 92).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [91] O'Leary, 2013, Adaptive plasticity of autophagic proteins to denervation in aging skeletal muscle, Am J Physiol Cell Physiol source

      Not checked in the free run.

    • cites [92] Russ, 2012, "Sr stress" in mixed hindlimb muscles of aging Male rats, Biogerontology source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Female rodents show higher endurance capacities and anti-fatigue properties than male rodents.

    “Additionally, previous studies have revealed that female rodents show higher endurance capacities and anti-fatigue properties than male rodents (107, 108).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [107] De Bono, 2006, Novel quantitative phenotypes of exercise training in mouse models, Am J Physiol Regulatory Integr Comp Physiol source

      Not checked in the free run.

    • cites [108] Dworatzek, 2014, Sex differences in exercise-induced physiological myocardial hypertrophy are modulated by oestrogen receptor beta, Cardiovasc Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Female mitochondria in the heart, liver, and brain have a higher antioxidant capacity and produce less ROS than males.

    “For instance, female mitochondria in the heart, liver, and brain have a higher antioxidant capacity and produce less ROS than males (101, 102).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [101] Khalifa, 2017, Sex-specific differences in mitochondria biogenesis, morphology, respiratory function, and ros homeostasis in young mouse heart and brain, Physiol Rep source

      Not checked in the free run.

    • cites [102] Borrás, 2003, Mitochondria from females exhibit higher antioxidant gene expression and lower oxidative damage than males, Free Radical Biol Med source

      Not checked in the free run.

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

    Premisecitation

    17β-estradiol can be produced locally from fat, brain, skeletal muscle, and testes by aromatization, which converts androstenedione and testosterone to 17β-estradiol.

    “It can also be produced locally from fat, brain, skeletal muscle, and testes by aromatization, which converts androstenedione and testosterone to 17β-estradiol (116, 117).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [116] Vermeulen, 2002, Estradiol in elderly men, Aging male source

      Not checked in the free run.

    • cites [117] Shi, 2019, Expression of aromatase and synthesis of sex steroid hormones in skeletal muscle following exercise training in ovariectomized rats, Steroids source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Female skeletal muscle has higher intracellular lipid content than males and may depend on fat oxidation to supply much more energy during exercise.

    “Moreover, female skeletal muscle has higher intracellular lipid content than males and thus may depend on fat oxidation to supply much more energy during exercise (110).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [110] Tarnopolsky, 2007, Influence of endurance exercise training and sex on intramyocellular lipid and mitochondrial ultrastructure, substrate use, and mitochondrial enzyme activity, Am J Physiol Regulatory Integr Comp Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activation of GPER is associated with the inhibition of mPTP opening, an effect mediated by the ERK pathway.

    “Activation of GPER is associated with the inhibition of mPTP opening, an effect mediated by the ERK pathway (125).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [125] Bopassa, 2010, A novel estrogen receptor gper inhibits mitochondria permeability transition pore opening and protects the heart against ischemia-reperfusion injury, Am J Physiol Heart Circulatory Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Sex differences in mitochondria include mitochondrial biogenesis, autophagy, susceptibility to mPTP opening, and cell apoptosis.

    “Other aspects of sex differences in mitochondria in different tissues include mitochondrial biogenesis, autophagy, susceptibility to mPTP opening, and cell apoptosis (111–113).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [111] Justo, 2005, Gender dimorphism in rat liver mitochondrial oxidative metabolism and biogenesis, Am J Physiol Cell Physiol source

      Not checked in the free run.

    • cites [112] Triolo, 2022, The influence of age, sex, and exercise on autophagy, mitophagy, and lysosome biogenesis in skeletal muscle, Skeletal Muscle source

      Not checked in the free run.

    • cites [113] Straface, 2015, Mitochondria can orchestrate sex differences in cell fate of vascular smooth muscle cells from rats, Biol sex Dif source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Overexpression of Parkin improves mitochondrial biogenesis and enzymatic activities.

    “In line, overexpression of Parkin attenuates aging-related loss of muscle mass and strength, along with improved mitochondrial biogenesis and enzymatic activities (95).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [95] Leduc-Gaudet, 2019, Parkin overexpression protects from ageing-related loss of muscle mass and strength, J Physiol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The biological effects of estrogen are mainly mediated via nuclear and membrane estrogen receptors (ERα, ERβ, and GPER), all three of which bind 17β-estradiol with high affinity in the low nM range.

    “The biological effects of estrogen are mainly mediated via nuclear and membrane estrogen receptors (ERs), including estrogen receptor α (ERα), estrogen receptor β (ERβ), and G-protein-coupled ER (GPR30 or GPER), all three bind 17β-estradiol with high affinity in the low nM range (118, 119).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [118] Kirker, 2013, High affinity nuclear and nongenomic estradiol binding sites in the human and mouse lens, Exp eye Res source

      Not checked in the free run.

    • cites [119] Revankar, 2005, A transmembrane intracellular estrogen receptor mediates rapid cell signaling, Science source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Castration leads to a decrease in mtDNA copy number in the skeletal muscle of male pigs, suggesting that testosterone is required to maintain mitochondrial copy number.

    “Castration leads to a decrease in mtDNA copy number in the skeletal muscle of male pigs, suggesting that testosterone is required to maintain mitochondrial copy number (146).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [146] Liu, 2019, Testosterone deficiency caused by castration modulates mitochondrial biogenesis through the Ar/Pgc1α/Tfam pathway, Front Genet source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exercise training can upregulate the expression of aromatase in rat skeletal muscle and increase the level of 17β-estradiol in skeletal muscle, which may be related to exercise improving skeletal muscle mass in OVX rat.

    “Interestingly, our previous studies have shown that exercise training can upregulate the expression of aromatase in rat skeletal muscle and increase the level of 17β-estradiol in skeletal muscle, which may be related to exercise improving skeletal muscle mass in OVX rat (117).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [117] Shi, 2019, Expression of aromatase and synthesis of sex steroid hormones in skeletal muscle following exercise training in ovariectomized rats, Steroids source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Data from the Women's Health Initiative (WHI) shows several risks of menopausal hormone therapy among healthy postmenopausal women, including an excess risk of coronary heart disease, stroke, and breast cancer.

    “Data from the Women’s Health Initiative (WHI) shows several risks of menopausal hormone therapy among healthy postmenopausal women, including an excess risk of coronary heart disease, stroke, and breast cancer (151).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [151] Rossouw, 2002, Risks and benefits of estrogen plus progestin in healthy postmenopausal women: Principal results from the women's health initiative randomized controlled trial, Jama source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both steroids trigger complex molecular mechanisms involving crosstalk between mitochondria, the nucleus, and the plasma membrane, and the result of this action is mitochondrial protection.

    “Both steroids trigger complex molecular mechanisms involving crosstalk between mitochondria, the nucleus, and the plasma membrane, and the result of this action is mitochondrial protection ( Figure 2 ).”
    Quote in the paperSubstantial claim

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

    Interpretationnone given

    Effective MQC machineries such as proteostasis, biogenesis, dynamics, and mitophagy work together to ensure that damaged or dysfunctional mitochondria are eliminated and replaced with healthy ones.

    “This largely depends on effective MQC machineries such as proteostasis, biogenesis, dynamics, and mitophagy, which work together to ensure that damaged or dysfunctional mitochondria are eliminated and replaced with healthy ones.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Castration increases LC3 II/I ratio in the skeletal muscle of male mice, indicating that androgen deficiency increases mitophagy.

    “In addition, Castration increases LC3 II/I ratio in the skeletal muscle of male mice, indicating that androgen deficiency increases mitophagy (147, 148).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [147] Rossetti, 2017, The role of androgens in the regulation of muscle oxidative capacity following aerobic exercise training, Appl physiology nutrition Metab = Physiologie appliquee Nutr metabolisme source

      Not checked in the free run.

    • cites [148] Rossetti, 2018, Increased mitochondrial turnover in the skeletal muscle of fasted, castrated mice is related to the magnitude of autophagy activation and muscle atrophy, Mol Cell Endocrinol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Knockout of AR results in the down-regulation of PGC-1α and TFAM in the muscle of castrated rats and mice, while the administration of exogenous androgen reversed these effects.

    “It has been reported that knockout of AR results in the down-regulation of PGC-1α and TFAM in the muscle of castrated rats and mice, while the administration of exogenous androgen reversed these effects (144, 145).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [144] Wang, 2015, Testosterone replacement attenuates mitochondrial damage in a rat model of myocardial infarction, J Endocrinol source

      Not checked in the free run.

    • cites [145] Rossetti, 2019, Disruptions to the limb muscle core molecular clock coincide with changes in mitochondrial quality control following androgen depletion, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

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

    Interpretationnone given

    Age-related muscle degeneration is caused when mitochondria are defective or abnormal and cannot be cleared or degraded effectively.

    “Age-related muscle degeneration is caused when mitochondria are defective or abnormal and cannot be cleared or degraded effectively.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Subpopulations of ERα and ERβ exist in mitochondria, although it is still unclear if they can directly regulate mtDNA transcription.

    “Interestingly, it was found that subpopulations of ERα and ERβ exist in mitochondria, although it is still unclear if they can directly regulate mtDNA transcription (132–134).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [132] Chen, 2004, Mitochondrial localization of eralpha and erbeta in human Mcf7 cells, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

    • cites [133] Milanesi, 2008, Expression and localization of estrogen receptor alpha in the C2c12 murine skeletal muscle cell line, J Cell Biochem source

      Not checked in the free run.

    • cites [134] Milanesi, 2009, Expression and subcellular distribution of native estrogen receptor beta in murine C2c12 cells and skeletal muscle tissue, Steroids source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Both 17β-estradiol and testosterone exert actions on mitochondria: they act directly on mitochondria, also through ERs and AR located in the organelle, and indirectly regulate nDNA-encoded mitochondrial proteins and nuclear transcription factors that affect mtDNA-encoded proteins.

    “Obviously, both 17β-estradiol and testosterone exert actions on mitochondria: 17β-estradiol and testosterone act directly on mitochondria, also through ERs and AR located in the organelle, and indirectly regulate nDNA-encoded mitochondrial proteins and nuclear transcription factors that affect mtDNA-encoded proteins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    While neither exercise nor nutrition can entirely treat the age-associated decline in muscular mass and strength, it can certainly slow down the development and reduce the rate of sarcopenia.

    “While neither exercise nor nutrition can entirely treat the age-associated decline in muscular mass and strength, it can certainly slow down the development and reduce the rate of sarcopenia (158).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [158] Beaudart, 2017, Nutrition and physical activity in the prevention and treatment of sarcopenia: Systematic review, Osteoporosis Int source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Testosterone may protect the respiratory chain of mitochondria from oxidative damage and maintain a normal OXPHOS function.

    “Moreover, testosterone may protect the respiratory chain of mitochondria from oxidative damage and maintain a normal OXPHOS function (149).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [149] Rottenberg, 2021, The mitochondrial permeability transition: Nexus of aging, disease and longevity, Cells source

      Not checked in the free run.

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

    Premisenone given

    Multiple factors, including dysregulation of mitochondrial OXPHOS, mutation or deletion of mtDNA, altered expression or function of mitochondria-associated proteins, imbalanced Ca2+ homeostasis, and ultrastructural defects, may cause mitochondrial dysfunction.

    “Multiple factors, including dysregulation of mitochondrial OXPHOS, mutation or deletion of mtDNA, altered expression or function of mitochondria-associated proteins, imbalanced Ca2+ homeostasis, and ultrastructural defects, may cause mitochondrial dysfunction.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Testosterone plays a crucial role in increasing protein synthesis and inhibiting muscle proteolysis in skeletal muscle.

    “As a principal anabolic hormone, testosterone plays a crucial role in increasing protein synthesis and inhibiting muscle proteolysis in skeletal muscle (140, 141).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [140] Rossetti, 2017, Androgen-mediated regulation of skeletal muscle protein balance, Mol Cell Endocrinol source

      Not checked in the free run.

    • cites [141] Howard, 2020, Testosterone supplementation upregulates androgen receptor expression and translational capacity during severe energy deficit, Am J Physiol Endocrinol Metab source

      Not checked in the free run.

42 of 42

  • The authors state this as an assumption.

    The exact mechanisms underlying sarcopenia are not fully understood.

    “Although the exact mechanisms underlying sarcopenia are not fully understood, evidence suggests that the loss of mitochondrial integrity in skeletal myocytes has emerged as a pivotal contributor to the complex etiology of sarcopenia.”

  • The authors state this as an assumption.

    The role of mitochondria in regulating motor neuron aging deficits or motor neuron death is not well understood.

    “Nevertheless, the role of mitochondria in regulating motor neuron aging deficits or motor neuron death is not well understood.”

  • The paper relies on this without support.

    Mitochondria are the main source of reactive oxygen species production in muscle and neuron cells.

    “As mentioned above, mitochondria were thought to the main source of ROS production.”

  • The paper relies on this without support.

    Aging causes a decrease in antioxidant enzyme levels in cells.

    “This is mainly attributed to the decrease of antioxidant enzymes level in cells caused by aging.”

  • The paper relies on this without support.

    Aging decreases mitochondrial function and mitochondrial content in skeletal muscle.

    “Aging decreases the mitochondrial function and mitochondrial content in the skeletal muscle.”

  • The paper relies on this without support.

    Aging increases mitochondrial stress, leading to increased sensitivity of the mitochondrial permeability transition pore opening.

    “Aging increases the levels of mitochondrial stress leading to the increased sensitivity of the mPTP opening.”

  • The paper relies on this without support.

    The mechanisms underlying mitochondrial dynamics alterations in aging muscle are poorly understood.

    “However, the mechanisms under these processes are still poorly understood.”

  • The paper relies on this without support.

    Circulating 17β-estradiol and testosterone decline with aging.

    “The decline in mitochondrial function and the reduction in circulating 17β-estradiol and testosterone that accompany aging may be two closely related processes.”

  • The paper relies on this without support.

    Almost all mitochondrial proteins are encoded in the nucleus and are influenced by sex chromosomes and circulating sex hormones.

    “Although mitochondria are inherited maternally, as mentioned above, almost all mitochondrial proteins are encoded in the nucleus and are therefore influenced by sex chromosomes and circulating sex hormones.”
9 of 9

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?

  • Mitochondrial abnormalities are common features of sarcopenia with aging, including disruptions in proteins responsible for mitochondrial fusion and fission, such as Mfn1/2, Opa1, Drp1, and Fis1.

    “mitochondrial abnormalities are common features of sarcopenia with aging, including disruptions in the proteins responsible for mitochondrial fusion and fission, such as mitofusin1/2 (Mfn1/2) that mediates OMM fusion, optic atrophy 1 (Opa1) that mediates IMM fusion, dynamin-related protein 1 (Drp1), and mitochondrial fission protein 1 (Fis1) [57].”

    From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [57]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

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

  • Estradiol's effect on bioenergetic function is stated in opposite directions

    Minor

    The text says 17β-estradiol reduces bioenergetic function, but the cited reference's title says it improves bioenergetic function. Both statements describe its direct effect in skeletal muscle.

1 of 1

Cites

Flagged first, then by citations

Cited by

Sorted by citations

Related

Authors
Tian, X., Lou, S., & Shi, R.
Affiliations
Shanghai University of Sport (CN)
Corresponding author
Shi, Rengfei
ORCID
Shi, Rengfei
Venue
Frontiers in Endocrinology
Publisher
Frontiers Media SA
Published
2023-04-20
Volume
14
Pages
1156583-1156583
ISSN
1664-2392 (ISSN-L)
DOI
10.3389/fendo.2023.1156583
PMC
PMC10157222
OpenAlex
W4366548377
Semantic Scholar
2c23b49e65a2338760482b3445d67a6c32f60a15
Cited by
54
References
160
Citations by year
2026: 18 · 2025: 17 · 2024: 12 · 2023: 7
FWCI
1.93
Type
journal article
Language
en
Open access
Licence
Locations
  • Frontiers in Endocrinology (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 (31971098, 32171136)
  • Natural Science Foundation of Shanghai (19ZR1452900)
Topics
  • Health Sciences › Medicine › Physiology › Nutrition and Health in Aging
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
Keywords
sarcopenia, mitochondrial dysfunction, estradiol, testosterone, sex hormones, aging, skeletal muscle, mitochondrial quality control, mitophagy, mitochondrial biogenesis, mitochondrial dynamics, reactive oxygen species, apoptosis, muscle mass and strength
MeSH terms
Aged, Estradiol, Humans, Mitochondria, Testosterone, Sarcopenia

About these checks

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

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

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

Statistics and arithmetic are recomputed, not judged.

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

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

Are you an author, or do you see a problem with this page? Request a review