Discovering pathways of sarcopenia in older adults: a role for insulin resistance on mitochondria dysfunction
Open accessAbstract
The precise cause of sarcopenia, skeletal muscle loss and strength, in older persons is unknown. However, there is a strong evidence for muscle loss due to insulin resistance as well as mitochondrial dysfunction over aging. Considering that epidemiological studies have underlined that insulin resistance may have a specific role on skeletal muscle fibre atrophy and mitochondrial dysfunction has also been extensively shown to have a pivotal role on muscle loss in older persons, a combined pathway may not be ruled out. Considering that there is growing evidence for an insulin-related pathway on mitochondrial signaling, we hypothesize that a high degree of insulin resistance will be associated with the development of sarcopenia through specific alterations on mitochondrial functioning. This paper will highlight recent reviews regarding the link between skeletal muscle mitochondrial dysfunction and insulin resistance. We will specifically emphasize possible steps involved in sarcopenia over aging, including potential biomolecular mechanisms of insulin resistance on mitochondrial functioning.
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Written from the paper’s full text.
TL;DR
This review hypothesizes that insulin resistance contributes to sarcopenia in older adults through specific impairments in skeletal muscle mitochondrial function. It synthesizes evidence that insulin regulates muscle mitochondrial gene expression, protein synthesis, and ATP production, while insulin-resistant and type 2 diabetic states show altered mitochondrial capacity.
Key findings
- The paper proposes a combined pathway in which high insulin resistance promotes sarcopenia via mitochondrial dysfunction, noting that InCHIANTI data showed insulin resistance increased with aging and was an independent determinant of weaker muscle strength, and HealthABC data showed excessive skeletal muscle mass loss in older adults with type 2 diabetes was two times faster than in those without diabetes.
- Mitochondrial dysfunction in aging muscle is characterized by electron transport chain abnormalities, accumulation of somatic mtDNA mutations, and increased oxidative stress; however, the literature on aging and skeletal muscle ETC function remains unclear, and physical inactivity may confound age-related reductions. Physically active older persons (average age 72±2 years) reportedly had normal mitochondrial ETC function despite increased oxidative damage compared with healthy young individuals (average age 22±3 years).
- Insulin appears to stimulate skeletal muscle mitochondrial function: acute insulin infusion in healthy middle-aged subjects increased mitochondrial transcript levels, protein synthesis, respiratory chain enzyme activity, and ATP production rate, while this acute stimulation of mitochondrial ATP production was not achieved by insulin in age-matched individuals with type 2 diabetes. Table 1 reports that in one cited study, mitochondrial oxidative and phosphorylation activity rates were reduced by ~40% in elderly versus young controls.
- The causal direction remains debated: insulin resistance may impair mitochondrial function, or mitochondrial dysfunction and ROS production may contribute to insulin resistance; the review also links skeletal muscle lipid infiltration/myosteatosis with insulin resistance and decreased muscle strength and physical performance in older persons.
Methods
- Narrative review and hypothesis paper; no primary data collection or new experimental study is reported.
- The paper synthesizes prior human and animal studies on sarcopenia, insulin resistance, and skeletal muscle mitochondrial function, including a table of selected studies with sample sizes, mean ages, insulin sensitivity techniques, and mitochondrial function assessments.
- Main analysis is conceptual synthesis rather than systematic review or meta-analysis; Table 1 includes human studies such as n=8 (age 21±1), n=16 (age 31±2), n=15 elders (age 70±2) versus n=13 young (age 27±2), and n=12 (age 24±1), plus animal studies in mice and rats.
Limitations
- The paper states that mechanisms explaining sarcopenia in older diabetics remain controversial, the relationship between mitochondrial ETC dysfunction, oxidative stress, and sarcopenia is unresolved, and whether reduced mitochondrial capacity is causative for insulin resistance or a consequence of it needs clarification.
- The paper states that the impact of an altered insulin pathway on mitochondrial activity in specific muscle fibers remains unknown, and data on older sarcopenic individuals with type 2 diabetes are lacking.
- Evident from the text: as a narrative review/hypothesis, it does not systematically search or quantitatively synthesize the literature, and the proposed causal pathway is not directly tested in a primary study.
Model-written summary. Check it against the paper before relying on it.
Integrity signals
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Cites
Statistics
Claims the paper makes
0 of 57 cited sources checked · 0 supported · 0 flagged
- Premisecitation
In older adults with type 2 diabetes, excessive loss of skeletal muscle mass is two times faster than in those without diabetes.
“In addition, data from the HealthABC study (2) showed an excessive loss of skeletal muscle mass in older adults with type 2 diabetes was two times faster than those without diabetes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [2] Park, 2009, Excessive loss of skeletal muscle mass in older adults with type 2 diabetes, Diabetes Care source
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- Premisecitation
A decline in aged skeletal muscle strength might be due to a reduction of L-type calcium channels.
“Furthermore, a decline in aged skeletal muscle strength might also be due to a reduction of L-type calcium channels (16).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [16] Boncompagni, 2006, Progressive disorganization of the excitation-contraction coupling apparatus in aging human skeletal muscle as revealed by electron microscopy: a possible role in the decline of muscle performance, J Gerontol A Biol Sci Med Sci source
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- Premisecitation
Recent studies show decreased activity of mitochondrial oxidative phosphorylation in skeletal muscle of type 2 diabetes.
“Recent studies have shown a decreased activity of mitochondrial oxidative phosphorylation in skeletal muscle of type 2 diabetes (3, 4).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [3] Wang, 2010, Impaired mitochondrial oxidative phosphorylation in multiple insulin-sensitive tissues of humans with type 2 diabetes mellitus, J Int Med Res
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- cites [4] Ritov, 2010, Deficiency of electron transport chain in human skeletal muscle mitochondria in type 2 diabetes mellitus and obesity, Am J Physiol Endocrinol Metab source
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- Premisecitation
Many studies have demonstrated a significant age-related reduction of mitochondrial ETC complex enzymes in human skeletal muscle.
“Many studies have demonstrated a significant age-related reduction of mitochondrial ETC complex enzymes in human skeletal muscle (21, 22).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [21] Hsieh, 1994, Age-dependent respiratory function decline and DNA deletions in human muscle mitochondria, Biochem Mol Biol Int
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- cites [22] Trounce, 1989, Decline in skeletal muscle mitochondrial respiratory chain function: possible factor in ageing, Lancet source
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- Premisecitation
Hyperinsulinemia in the high-physiological range increased transcript levels of complex I and complex IV subunits of the respiratory chain.
“Hyperinsulinemia in the high–physiological range increased transcript levels of complex I and complex IV subunits of the respiratory chain (28).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [28] Huang, 1999, Insulin-regulated mitochondrial gene expression is associatedwith glucose flux in human skeletal muscle, Diabetes source
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- Interpretationcitation
Insulin selectively enhances muscle mitochondrial protein synthesis in vivo.
“Indeed these findings indicate a specific effect of insulin on selectively enhancing muscle mitochondrial protein synthesis in vivo.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Boirie, 2001, Tissue-specific regulation of mitochondrial and cytoplasmic protein synthesis rates by insulin, Diabetes source
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- Interpretationnone given
A vicious circle connects insulin action and an age-related decline in physical activity that progressively aggravates insulin resistance.
“Second, a vicious circle connects insulin action and an age-related decline in physical activity that progressively aggravates the degree of insulin resistance.”
Quote in the paperNot a substantial claim - Premisecitation
Contraction of type I fibers is more dependent on glucose entry and metabolism than contraction of type IIa or IIb fibers.
“The contraction of type I fibers is more dependent on glucose entry and metabolism than is the contraction of type IIa (fast twitch, oxidative, glycolytic) or IIb (fast twitch, glycolytic) fibers (11).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Song, 1999, Muscle fiber type specificity in insulin signal transduction, Am J Physiol
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- Premisecitation
When insulin was infused into healthy middle-aged subjects, mitochondrial transcript levels, protein synthesis, respiratory chain enzyme activity and ATP production rate all significantly increased.
“When insulin was infused into healthy middle-aged subjects, mitochondrial transcript levels, protein synthesis, respiratory chain enzyme activity and the ATP production rate all significantly increased (30).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Stump, 2003, Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts, Proc Natl Acad Sci USA source
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- Premisecitation
Age-related changes of hormonal regulation play a role in pathophysiological mechanisms implicated in the pathogenesis of sarcopenia.
“There is growing evidence that age-related changes of hormonal regulation play a role in pathophysiological mechanisms implicated in the pathogenesis of sarcopenia (10).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [10] Short, 2005, Decline in skeletal muscle mitochondrial function with aging in humans, Proc Nat Acad Sci USA source
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- Premisecitation
Deficiency in the mitochondrial electron transport chain in muscle does not cause insulin resistance.
“However, there is very recent data indicating that a deficiency in the mitochondrial electron transport chain (ETC) in muscle does not cause insulin resistance (42) in contrast to the potential mechanism of “mitochondrial deficiency” in which it is hypothesized that insulin resistance is caused by an accumulation of intramuscular lipids as a result of decreased capacity for fat oxidation (43).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Han, 2011, Deficiency of the mitochondrial electron transport chain in muscle does not cause insulin resistance, PLoS source
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- Interpretationcitation
The stimulatory effect of insulin on mitochondrial protein synthesis seems specific to skeletal muscle.
“Considering that liver mitochondrial protein synthesis tended to be lower during hyperinsulinemia, the stimulatory effect of insulin seems to be specific to skeletal muscle (31).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Boirie, 2001, Tissue-specific regulation of mitochondrial and cytoplasmic protein synthesis rates by insulin, Diabetes source
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- Premisecitation
Age-associated alterations have been reported in skeletal muscle at both transcriptional and functional levels of mitochondrial gene expression.
“Age-associated alterations have been reported in skeletal muscle at both transcriptional and functional levels of mitochondrial gene expression (27).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [27] Barazzoni, 2000, Effects of aging on mitochondrial DNA copy number and cytochrome c oxidase gene expression in rat skeletal muscle, liver and heart, J Biol Chem source
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- Premisecitation
Acute intravenous insulin infusion in an animal model enhances mitochondrial protein synthesis rate in a tissue-specific fashion.
“Acute intravenous insulin infusion in an animal model was shown to enhance the mitochondrial protein synthesis rate in a tissue-specific fashion (31).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Boirie, 2001, Tissue-specific regulation of mitochondrial and cytoplasmic protein synthesis rates by insulin, Diabetes source
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- Interpretationcitation
Insulin is a stimulator of muscle mitochondrial function in vivo in humans.
“This important study introduced the theory that insulin is a stimulator of muscle mitochondrial function in vivo in humans.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Stump, 2003, Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts, Proc Natl Acad Sci USA source
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- Premisecitation
Increased mitochondrial protein synthesis from insulin is not associated with increments in synthesis rates of other muscle protein pools, including sarcoplasmic protein and myosin heavy chain.
“In addition, these authors showed that such increased mitochondrial protein synthesis was not associated with increments in the synthesis rates of other muscle protein pools, including sarcoplasmic protein and major contractile protein myosin heavy chain (31).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Boirie, 2001, Tissue-specific regulation of mitochondrial and cytoplasmic protein synthesis rates by insulin, Diabetes source
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- Premisecitation
Age-related decreases in functionally intact mitochondria with decline in ATP production, energy-dependent protein synthesis and increased peroxide leakage may contribute to muscle loss.
“Age-related decreases in the amount of functionally intact mitochondria with concomitant decline in cellular production of adenosinetriphosphate (ATP), energy-dependent protein synthesis and increased peroxide leakage may contribute to muscle loss (25).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [25] Castillo, 2003, Sarcopenia in elderly men and women: the Rancho Bernardo study, Am J Prev Med source
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- Premisecitation
During aging, changes in contractile efficiency of muscle fibers and tissue quality, such as pericellular fat infiltration, may contribute to altered muscle function.
“During the aging process, changes both in the contractile efficiency of muscle fibers and in tissue quality, such as pericellular fat infiltration, may also contribute to altered muscle function (12, 13).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [12] Lexell, 1983, Distribution of aging studied in whole muscle cross-sections, Muscle Nerve source
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- cites [13] Madsen, 1997, Muscle strength and soft tissue composition as measured by dual energy x-ray absorptiometry in women aged 18–87 years, Eur J Appl Physiol Occup Physiol source
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- Interpretationcitation
An altered mitochondrial response to insulin could contribute to impaired substrate utilization, as an integral component of insulin resistance in type 2 diabetes.
“An altered mitochondrial response to insulin could therefore contribute to impaired substrate utilization, as an integral component of insulin resistance in this disease.”
Quote in the paperSubstantial claim - Premisecitation
Insulin resistance in skeletal muscle in obesity or type 2 diabetes is associated with reduced muscle oxidative capacity.
“Insulin resistance in skeletal muscle in obesity or type 2 diabetes is associated with reduced muscle oxidative capacity (54).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [54] Simoneau, 1997, Altered glycolytic and oxidative capacities of skeletal muscle contribute to insulin resistance in NIDDM, J Appl Physiol source
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- Premisecitation
The authors of a recent study did not determine the type of muscle fiber in relation to mitochondria and insulin resistance.
“Even though a recent study speculated that the defects in mitochondrial content/morphology in aging occurred independently of insulin resistance, the authors did not determine the type of muscle fiber in relation to mitochondria and insulin resistance (53).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [53] Corcoran, 2007, Skeletal muscle lipid deposition and insulin resistance: effect of dietary fatty acids and exercise, Am J Clin Nutr source
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- Interpretationreasoning
New data promote a direct role of insulin resistance pathways on mitochondrial dysfunction.
“new data promote a direct role of insulin resistance pathways on mitochondrial dysfunction.”
Quote in the paperNot a substantial claim - Interpretationcitation
Lower oxidative capacity may also result from insulin resistance and high intramyocellular triglycerides by lipotoxic measures.
“However, lower oxidative capacity may also result from insulin resistance and high intramyocellular triglycerides by lipotoxic measures.”
Quote in the paperSubstantial claim - Interpretationreasoning
Mitochondrial defects occur in type 2 diabetes, in particular in skeletal muscle.
“As insulin resistance characterizes type 2 diabetes, it is conceivable that mitochondrial defects occur in this disease, in particular in skeletal muscle.”
Quote in the paperSubstantial claim- Rests on an assumption: Insulin resistance characterizes type 2 diabetes.
- Premisecitation
The acute stimulation of mitochondrial ATP production observed in healthy individuals was not achieved by insulin in age-matched individuals with type 2 diabetes.
“The study by Stump et al (30) provided further important evidence in this regard by demonstrating that the acute stimulation of mitochondrial ATP production observed in healthy individuals was not achieved by insulin in age-matched individuals with type 2 diabetes.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [30] Stump, 2003, Effect of insulin on human skeletal muscle mitochondrial ATP production, protein synthesis, and mRNA transcripts, Proc Natl Acad Sci USA source
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- Interpretationreasoning
A specific role played by insulin resistance in sarcopenia cannot be overruled.
“Considering that type I fibers are more responsive to insulin and have a greater mitochondrial content, a specific role played by insulin resistance in sarcopenia cannot be overruled.”
Quote in the paperSubstantial claim- Rests on an assumption: Type I fibers are more responsive to insulin and have a greater mitochondrial content.
- Interpretationcitation
A defective response of skeletal muscle mitochondria to acute insulin-induced stimulation occurs in humans with type 2 diabetes.
“A defective response of skeletal muscle mitochondria to acute insulin-induced stimulation occurs in humans with type 2 diabetes.”
Quote in the paperSubstantial claim - Premisecitation
Accumulating fatty acids within myocytes interact with ROS-forming peroxides, which lead to lipotoxic effects on mitochondria.
“In particular, accumulating fatty acids within myoctyes interact with ROS-forming peroxides which in turn lead to lipotoxic effects on mitochondria (26).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Hoeks, 2010, Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance, Diabetes source
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- Premisenone given
Insulin plays a role in regulating the efficiency of ATP production, especially in muscle cells.
“Even though it was originally believed that thyroid hormones were solely responsible for energy production within mitochondria, we have underlined that recent studies have also show that insulin also plays a role in regulating the efficiency of ATP production especially in muscle cells.”
Quote in the paperNot a substantial claim
- May combine two claims. 25
- Classified as probably not a substantial claim. 4
May combine two claims.
PremisecitationIn older persons, insulin resistance increases substantially with aging and is an independent determinant of weaker muscle strength.
“Data from the InCHIANTI study showed that insulin resistance substantially increased with aging and was an independent determinant of weaker muscle strength in older persons (1).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [1] Abbatecola, 2005, Insulin resistance and muscle strength in older persons, J Gerontol A Biol Sci Med Sci source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe role of mitochondrial dysfunction in the etiology of sarcopenia has been extensively characterized.
“The role of mitochondrial dysfunction in the etiology of sarcopenia has been extensively characterized (17, 18, 19, 20).”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [17] Aiken, 2002, Mitochondrial DNA deletion mutations and sarcopenia, Ann N Y Acad Sci source
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- cites [18] Bua, 2006, Mitochondrial DNA-deletion mutations accumulate intracellularly to detrimental levels in aged human skeletal muscle fibers, Am J Hum Genet source
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- cites [19] Bua, 2002, Mitochondrial abnormalities are more frequent in muscles undergoing sarcopenia, J Appl Physiol source
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- cites [20] Wanagat, 2001, Mitochondrial DNA deletion mutations colocalize with segmental electron transport system abnormalities, muscle fiber atrophy, fiber splitting, and oxidative damage in sarcopenia, Faseb J source
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAge-associated skeletal muscle alterations are a major risk factor for falls, fractures and loss of independence in older persons.
“These alterations represent a major risk factor for falls, fractures and loss of independence in older persons (7).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [7] Wolfson, 1995, Strength is a major factor in balance, gait, and the occurrence of falls, J Gerontol source
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PremisecitationThere are reports on altered mitochondrial adaptations in skeletal muscle during development of insulin resistance in adults, as well as improvement in mitochondrial capacity to oxidize fat-derived substrates and increase in number.
“There have also been reports on altered mitochondrial adaptations in skeletal muscle during the development of insulin resistance in adults (36, 37), as well as an improvement in mitochondrial capacity to oxidize fat-derived substrates and increase in number (38).”
Quote in the paperNot a substantial claim0 of 3 sources checked- cites [36] Barletta, 2003, Effect of high-fat feeding on metabolic efficiency and mitochondrial oxidative capacity in adult rats, Br. J. Nutr. source
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- cites [37] Bonnard, 2008, Mitochondrial dysfunction results from oxidative stress in the skeletal muscle of diet-induced insulin-resistant mice, J Clin Invest
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- cites [38] Hancock, 2008, High-fat diets cause insulin resistance despite an increase in muscle mitochondria, Proc. Natl. Acad. Sci. USA source
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InterpretationreasoningInsulin has a stimulatory effect on intracellular calcium uptake, so insulin resistance may negatively affect muscle contraction through this mechanism.
“Insulin has a stimulatory effect on intracellular calcium uptake, thus insulin resistance may negatively affect muscle contraction through this mechanism.”
Quote in the paperNot a substantial claim- Rests on an assumption: Insulin plays a pivotal role in muscle functioning by increasing glucose uptake and promoting intracellular glucose metabolism.
May combine two claims.
InterpretationcitationMuscle from older adults shows increased mitochondrial ETC abnormalities, accumulation of somatic mtDNA mutations, and increased markers of oxidative stress.
“Muscle from older adults have shown: i) an increase in mitochondrial ETC abnormalities marked by the accumulation of cytochrome c oxidase negative and succinate dehydrogenase hyper-positive fibres, ii) accumulation of somatic mtDNA mutations iii) an increase in markers of oxidative stress.”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationAn increased proteolytic state, commonly observed in older persons, reflects depletion in protein activity and is associated with impaired mobility and balance, suggesting a link with sarcopenia.
“An increased proteolytic state, commonly observed in older persons, reflects a significant depletion in protein activity and has been reported to be associated with risk factors related to muscle strength and function, such as impaired mobility and balance, suggesting a link with sarcopenia (15).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [15] Rolland, 2008, Sarcopenia: its assessment, etiology, pathogenesis, consequences and future perspectives, J Nutr Health Aging source
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InterpretationcitationMitochondrial dysfunction causes production of ROS, which begins a vicious cycle with insulin resistance.
“This differences lies in the fact that mitochondrial dysfunction causes the production of ROS which in turn begin a vicious cycle with insulin resistance.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationnone givenAging is modulated by ROS-mediated toxicity leading to mtDNA deletions and mutations, macromolecular oxidation, ETC dysfunction, cellular senescence and cell death.
“The “mitochondrial dysfunction on muscle over aging” highlights that the aging process is modulated by reactive oxygen species (ROS)-mediated toxicity leading to mitochondrial DNA (mtDNA) deletions and mutations, macromolecular oxidation, electron transport chain (ETC) dysfunction, cellular senescence and cell death.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationLipid infiltration is an important determinant of insulin resistance in healthy and diseased patients; it is independent of visceral fat and is associated with decreased muscle strength and physical performance in older persons.
“As determined by the computerized tomography (CT) attenuation coefficient of muscle, lipid infiltration is an important determinant of insulin resistance in healthy (45) and diseased patients (46): it is independent of visceral fat and is associated with decreased muscle strength and physical performance in older persons (47).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [45] Goodpaster, 1997, Subcutaneous abdominal fat and thigh muscle composition predict insulin sensitivity independently of visceral fat, Diabetes source
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- cites [46] Torriani, 2003, Psoas muscle attenuation measurement with computed tomography indicates intramuscular fat accumulation in patients with HIV-lipodystrophy syndrome, J Appl Physiol source
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- cites [47] Goodpaster, 2001, Attenuation of skeletal muscle and strength in the elderly. The Health ABC study, J Appl Phsiol source
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May combine two claims.
PremisecitationLower HU reflects higher intramuscular lipid content and has been used as a reliable parameter in studies on sarcopenia.
“Lower HU reflects higher intramuscular lipid content, and has been used as a reliable parameter in a number of studies on sarcopenia (47-48).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [47] Goodpaster, 2001, Attenuation of skeletal muscle and strength in the elderly. The Health ABC study, J Appl Phsiol source
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- cites [48] Abbatecola AM, Chiodini P, Gallo C, Lakatta E, Sutton-Tyrrell K, Tylavsky FA, Goodpaster B, de Rekeneire N, Schwartz AV, Paolisso G, Harris T; for the Health ABC study (2011) Pulse wave velocity is associated with muscle mass decline: Health ABC study. Age (Dordr).
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May combine two claims.
PremisecitationIntervention studies on physical activity and mitochondrial function report parallel increases in response to training with a weak relation between mitochondrial activity and insulin sensitivity in older persons.
“Intervention studies on physical activity and mitochondrial function report parallel increases in response to training with a weak relation between mitochondrial activity and insulin sensitivity in older persons (39).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [39] Short, 2003, Impact of aerobic exercise training on age-related changes in insulin sensitivity and muscle oxidative capacity, Diabetes source
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PremisecitationDietary fat induced insulin resistance results from increased mitochondrial H2O2 production and is prevented by mitochondrial targeted antioxidant or overexpression of catalase.
“Anderson et al. (41) demonstrated that dietary fat induced insulin resistance results from increased mitochondrial H2O2 production and this insulin resistance is prevented by use of a mitochondrial targeted antioxidant or overexpression of catalase.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [41] Anderson, 2009, Mitochondrial H2O2 emission and cellular redox state link excess fat intake insulin reisistance in both rodents and humans, J Clin Invest source
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InterpretationreasoningAge-related insulin resistance is associated with impaired muscle glucose handling, which impairs intracellular energy production and results in weaker muscle contraction.
“First, age-related insulin resistance is associated with impaired muscle glucose handling that in turn impairs intracellular energy production and results in weaker muscle contraction.”
Quote in the paperSubstantial claim- Rests on an assumption: Insulin plays a pivotal role in muscle functioning by increasing glucose uptake and promoting intracellular glucose metabolism.
May combine two claims.
PremisecitationBasal ATP synthesis rates in skeletal muscle are lower in insulin resistant subjects, and insulin resistant states show dysfunctional mitochondria with down-regulation of genes encoding mitochondrial enzymes, decreased mitochondrial content, and lower respiratory chain activity.
“It has been observed that basal ATP synthesis rates in skeletal muscle are lower in insulin resistant subjects (32) and studies have provided evidence for dysfunctional mitochondria in insulin resistant states as seen by a down-regulation of genes encoding for mitochondrial enzymes 33, 34 decreased mitochondrial content and lower respiratory chain activity (35).”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [32] Petersen, 2003, Mitochondrial dysfunction in the elderly: possible role in insulin resistance, Science source
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- cites [33] Mootha, 2003, PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes, Nat. Genet. source
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- cites [34] Patti, 2003, Coordinated reduction of genes of oxidative metabolism in humans with insulin resistance and diabetes: Potential role of PGC1 and NRF1, Proc. Natl. Acad. Sci. U. S. A. source
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PremisecitationMuscle attenuation in Hounsfield Units obtained by CT is a non-invasive measure of muscle density and correlates with intramuscular lipid content obtained by muscle biopsy.
“Muscle attenuation in Hounsfield Units (HU) obtained by CT is a non-invasive measure of muscle density and correlates with intramuscular lipid content obtained by muscle biopsy (47, 48).”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [47] Goodpaster, 2001, Attenuation of skeletal muscle and strength in the elderly. The Health ABC study, J Appl Phsiol source
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- cites [48] Abbatecola AM, Chiodini P, Gallo C, Lakatta E, Sutton-Tyrrell K, Tylavsky FA, Goodpaster B, de Rekeneire N, Schwartz AV, Paolisso G, Harris T; for the Health ABC study (2011) Pulse wave velocity is associated with muscle mass decline: Health ABC study. Age (Dordr).
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Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIt has been suggested that age-related reduction in ETC function is not related to aging per se, but due to confounding factors including physical inactivity.
“However, it has also been suggested that the age-related reduction in ETC function, reduced mitochondrial complex I, II, III, and IV activity, is not related to the aging process per se, but rather due to other confounding factors, including physical inactivity (23).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [23] Barrientos, 1996, Absence of relationship between the level of electron transport chain activities and aging in human skeletal muscle, Biochem Biophys Res Commun source
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PremisecitationIn obese type 2 diabetic subjects compared to non-obese diabetics, altered fat acid oxidation and lipid storage, impaired insulin signaling and insulin resistance were associated with significantly lower mitochondrial phosphorylation capacity.
“Interestingly, a significant role altered fat acid oxidation and lipid storage, impaired insulin signaling and insulin resistance were associated significantly lower mitochondrial phosphorylation capacity in obese type 2 diabetic subjects compared to non-obese diabetics (44), thus strengthening the hypothesis that insulin resistance has a direct role on mitochondrial functional impairment.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [44] Chattopadhyay M, Guhathakurta I, Behera P, Ranjan KR, Khanna M, Mukhopadhyay S, Chakrabarti S. (2011) Mitochondrial bioenergetics is not impaired in nonobese subjects with type 2 diabetes mellitus. Metabolism. source
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Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationSarcopenia is characterized by a decrease in total number of skeletal muscle fibers, reduced cross-sectional area of the thigh, and increased intramuscular fat content.
“Sarcopenia, loss of muscle mass, is characterized by a decrease in the total number of skeletal muscle fibers, reduced cross-sectional area of the thigh, and an increase in intramuscular fat content (8).”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Evans, 1997, Nutrition, exercise, and healthy aging, J Am Diet Assoc source
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PremisecitationInsulin resistance could be worsened by pericellular fat accumulation directly and through increased production of pro-inflammatory cytokines such as TNF- and IL-6, which are associated with lower muscle mass and strength.
“Moreover, insulin resistance could be further worsened by the occurrence of pericellular fat accumulation both directly and through the increased production of pro-inflammatory cytokines such as TNF- and IL-6 that in turn have been associated with lower muscle mass and strength (14).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [14] Cesari, 2006, Frailty syndrome and skeletal muscle: results from the Invecchiare in Chianti study, Am J Clin Nutr source
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PremisecitationMitochondrial oxidative capacity is decreased in skeletal muscle of obese individuals and is considered a consequence of insulin resistance in humans.
“Mitochondrial oxidative capacity is decreased in skeletal muscle of obese individuals and is considered a consequence of insulin resistance in humans (26).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [26] Hoeks, 2010, Prolonged fasting identifies skeletal muscle mitochondrial dysfunction as consequence rather than cause of human insulin resistance, Diabetes source
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InterpretationreasoningAge-related insulin resistance may define protein catabolism and muscle weakness.
“Therefore, age-related IR may define protein catabolism and muscle weakness.”
Quote in the paperSubstantial claim- Rests on an assumption: Insulin is capable of preventing protein breakdown by increasing amino acid availability needed for protein synthesis in muscle tissue.
May combine two claims.
PremisecitationIncrements in mitochondrial transcripts were positively related to insulin-mediated glucose disposal, supporting that muscle mitochondria are mediators of insulin action to increase glucose utilization.
“Interestingly, increments in mitochondrial transcripts were positively related to those of insulin-mediated glucose disposal (29), supporting the hypothesis that muscle mitochondria are mediators of insulin action to increase glucose utilization.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [29] Huang, 1999, Insulin-regulated mitochondrial gene expression is associated with glucose flux in human skeletal muscle, Diabetes source
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May combine two claims.
PremisecitationAge-associated skeletal muscle dysfunction includes reduction of muscle mass, strength, and endurance capacity.
“Age-associated skeletal muscle dysfunction has been well characterized and includes a reduction of muscle mass, strength and, according to several studies, endurance capacity (5, 6).”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [5] Lennmarken, 1985, Skeletal muscle function in man: force, relaxation rate, endurance and contraction time-dependence on sex and age, Clin Physiol source
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- cites [6] Jubrias, 1997, Decline in isokinetic force with age: muscle cross-sectional area and specific force, Arch Eur J Physiol source
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May combine two claims.
PremisecitationType I fibers are more responsive to insulin and more represented in the muscle of older persons.
“Type I fibers are more responsive to insulin and more represented in the muscle of older persons (11).”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [11] Song, 1999, Muscle fiber type specificity in insulin signal transduction, Am J Physiol
Not checked in the free run.
May combine two claims.
InterpretationreasoningMitochondrial dysfunction is associated with insulin resistance and type 2 diabetes.
“In conclusion, mitochondrial dysfunction is associated with insulin resistance and type 2 diabetes.”
Quote in the paperNot a substantial claimMay combine two claims.
PremisecitationThere are data supporting that insulin resistance in humans arises from defects in mitochondrial fatty acid oxidation, leading to increase in intracellular fatty acid metabolites capable of interfering with insulin signaling.
“Indeed there are data that support the hypothesis that insulin resistance in humans arises from defects in mitochondrial fatty acid oxidation (32), which leads to an increase in intracellular fatty acid metabolites (acyl CoA and diacylglyerol) capable of interfering with the insulin signaling pathway (49).”
Quote in the paperSubstantial claim0 of 2 sources checkedMay combine two claims.
InterpretationreasoningMitochondrial dysfunction, due to altered insulin signaling, may have a crucial role in aging and in particular in patients with type 2 diabetes.
“The mechanisms explaining the development of sarcopenia in older diabetics remain controversial, however mitochondrial dysfunction, due to altered insulin signaling, may have a crucial role in aging and in particular in patients with type 2 diabetes.”
Quote in the paperSubstantial claim
The paper relies on this without support.
The precise cause of sarcopenia in older persons is unknown.
“The precise cause of sarcopenia, skeletal muscle loss and strength, in older persons is unknown.”
The paper relies on this without support.
The mechanisms leading to skeletal muscle mass loss over aging and in older persons with diabetes are lacking.
“Unfortunately, up to date the mechanisms leading to skeletal muscle mass loss over aging and in particular in older persons with diabetes are lacking.”
The paper relies on this without support.
Insulin plays a pivotal role in muscle functioning by increasing glucose uptake and promoting intracellular glucose metabolism.
“Insulin is known to play a pivotal role in muscle functioning by increasing glucose uptake and promoting intracellular glucose metabolism.”
The paper relies on this without support.
Insulin is capable of preventing protein breakdown by increasing amino acid availability needed for protein synthesis in muscle tissue.
“It is well known that insulin is capable of preventing protein breakdown by increasing amino acid availability needed for protein synthesis in muscle tissue.”
The paper relies on this without support.
Skeletal muscle is a key metabolic organ and the major site of insulin-mediated glucose disposal.
“Skeletal muscle is a key metabolic organ and the major site of insulin-mediated glucose disposal, plays an important role in the metabolic alterations of insulin signaling.”
The paper relies on this without support.
The relationship between mitochondrial ETC dysfunction, oxidative stress and sarcopenia remains unresolved and may be influenced by factors other than aging alone.
“Hence, the relationship between mitochondrial ETC dysfunction, oxidative stress and sarcopenia remains an important and unresolved issue in aging research that may be influenced by factors other than aging alone.”
The paper relies on this without support.
The literature on the effect of aging on skeletal muscle ETC function remains unclear in humans.
“Despite a strong relationship between aging and oxidative damage, the literature on the effect of aging on skeletal muscle ETC function remains unclear in humans.”
The paper relies on this without support.
Whether reduced mitochondrial capacity in skeletal muscle is causative for insulin resistance or arises as a consequence of insulin resistance impacting muscle loss needs to be clarified.
“However, whether reduced mitochondrial capacity in skeletal muscle is causative for insulin resistance or, instead, arises as a consequence of insulin resistance impacting muscle loss needs to be clarified.”
The paper relies on this without support.
Insulin resistance characterizes type 2 diabetes.
“As insulin resistance characterizes type 2 diabetes, it is conceivable that mitochondrial defects occur in this disease, in particular in skeletal muscle.”
The paper relies on this without support.
Type I fibers are more responsive to insulin and have a greater mitochondrial content.
“Considering that type I fibers are more responsive to insulin and have a greater mitochondrial content, a specific role played by insulin resistance in sarcopenia cannot be overruled.”
The paper relies on this without support.
Insulin resistance leads to type 2 diabetes.
“Insulin resistance, that also leads to type 2 diabetes, has been considered to be responsible of the development of skeletal muscle lipid deposition that also characterizes sarcopenia as a consequence of severe fat infiltration.”
The paper relies on this without support.
Data on older sarcopenic individuals with type 2 diabetes are lacking.
“Some studies have reported no difference between muscle fiber type and mitochondrial function, however data on older sarcopenic individuals with type 2 diabetes are lacking.”
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?
The loss of muscle strength and the gain of fat which characterize sarcopenic obesity is attributed by insulin resistance.
“Hence, the loss of muscle strength and the gain of fat which characterize SO is attributed by insulin resistance (41).”
From Diabetes and Sarcopenic Obesity: Pathogenesis, Diagnosis, and Treatments (2020) · cites this paper as [41]
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- Authors
- Abbatecola, A. M., Paolisso, G., Fattoretti, P., Evans, W. J., Fiore, V., Dicioccio, L., & Lattanzio, F.
- Affiliations
- Istituto Nazionale di Riposo e Cura per Anziani (IT)
- University of Campania "Luigi Vanvitelli" (IT)
- GlaxoSmithKline (United States) (US)
- Corresponding author
- Abbatecola, Angela Marie
- Venue
- The Journal of nutrition, health and aging
- Publisher
- Elsevier BV
- Published
- 2011-12
- Volume
- 15
- Issue
- 10
- Pages
- 890-895
- ISSN
- 1279-7707 (ISSN-L)
- PMC
- PMC12878137
- OpenAlex
- W2084965695
- Semantic Scholar
- 9b3c85a46b4b2d456ba95af216ae3453faccda32
- Cited by
- 137
- References
- 57
- Citations by year
- 2026: 6 · 2025: 13 · 2024: 9 · 2023: 13 · 2022: 8 · 2021: 11 · 2020: 7 · 2019: 10 · 2018: 10 · 2017: 9 · 2016: 6 · 2015: 7 · 2014: 9 · 2013: 8 · 2012: 9
- FWCI
- 0.89
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- The journal of nutrition health & aging (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- 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, insulin resistance, mitochondrial dysfunction, skeletal muscle atrophy, muscle fiber atrophy, aging, older adults, mitochondrial signaling, biomolecular mechanisms
- MeSH terms
- Aged, Aging, Humans, Insulin Resistance, Mitochondria, Muscular Atrophy, Muscle, Skeletal, Muscle Strength, 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 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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