Age-Related DNA Methylation Changes: Potential Impact on Skeletal Muscle Aging in Humans

Skeletal muscle aging is associated with a significant loss of skeletal muscle strength and power (i.e., dynapenia), muscle mass and quality of life, a phenomenon known as sarcopenia. This condition affects nearly one-third of the older population and is one of the main factors leading to negative health outcomes in geriatric patients. Notwithstanding the exact mechanisms responsible for sarcopenia are not fully understood, mitochondria have emerged as one of the central regulators of sarcopenia. In fact, there is a wide consensus on the assumption that the loss of mitochondrial integrity in myocytes is the main factor leading to muscle degeneration. Mitochondria are also key players in senescence. It has been largely proven that the modulation of mitochondrial functions can induce the death of senescent cells and that removal of senescent cells improves musculoskeletal health, quality, and function. In this review, the crosstalk among mitochondria, cellular senescence, and sarcopenia will be discussed with the aim to elucidate the role that the musculoskeletal cellular senescence may play in the onset of sarcopenia through the mediation of mitochondria.

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Exercise rescues mitochondrial coupling in aged skeletal muscle: a comparison of different modalities in preventing sarcopenia

Journal of Translational Medicine ◽

10.1186/s12967-021-02737-1 ◽

2021 ◽

Vol 19 (1) ◽

Author(s):

Colin Harper ◽

Venkatesh Gopalan ◽

Jorming Goh

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Function ◽

Fiber Type ◽

Skeletal Muscle Function ◽

Atp Production ◽

Muscle Aging ◽

Age Related ◽

Key Factor ◽

Underlying Mechanisms ◽

Skeletal Muscle Aging

AbstractSkeletal muscle aging is associated with a decline in motor function and loss of muscle mass- a condition known as sarcopenia. The underlying mechanisms that drive this pathology are associated with a failure in energy generation in skeletal muscle, either from age-related decline in mitochondrial function, or from disuse. To an extent, lifelong exercise is efficacious in preserving the energetic properties of skeletal muscle and thus may delay the onset of sarcopenia. This review discusses the cellular and molecular changes in skeletal muscle mitochondria during the aging process and how different exercise modalities work to reverse these changes. A key factor that will be described is the efficiency of mitochondrial coupling—ATP production relative to O2 uptake in myocytes and how that efficiency is a main driver for age-associated decline in skeletal muscle function. With that, we postulate the most effective exercise modality and protocol for reversing the molecular hallmarks of skeletal muscle aging and staving off sarcopenia. Two other concepts pertinent to mitochondrial efficiency in exercise-trained skeletal muscle will be integrated in this review, including- mitophagy, the removal of dysfunctional mitochondrial via autophagy, as well as the implications of muscle fiber type changes with sarcopenia on mitochondrial function.

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Skeletal muscle aging

Reviews in Clinical Gerontology ◽

10.1017/s0959259808002360 ◽

2007 ◽

Vol 17 (1) ◽

pp. 13-23 ◽

Cited By ~ 2

Author(s):

Graeme L Close ◽

Philippa Haggan ◽

Anne McArdle

Keyword(s):

Skeletal Muscle ◽

Life Expectancy ◽

Muscle Function ◽

Active Life Expectancy ◽

Active Life ◽

Muscle Aging ◽

Age Related ◽

Dramatic Rise ◽

Skeletal Muscle Aging

Average world life expectancy has seen a dramatic rise over the last two centuries although active life expectancy remains relatively unchanged. One reason for this is that aging results in skeletal muscle becoming smaller, weaker and more susceptible to contraction-induced injury. By the age of 70, muscle strength is reduced by around 30–40% and this can have catastrophic effects on quality of life. Despite a vast amount of research into age-related changes in skeletal muscle, the exact mechanisms responsible for this is still unclear and thus treatments to preserve muscle function with aging remain elusive.

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Lifelong Ulk1-mediated autophagy deficiency in muscle induces mitochondrial dysfunction and contractile weakness

10.1101/2020.07.31.223412 ◽

2020 ◽

Author(s):

Anna S. Nichenko ◽

Jacob R. Sorensen ◽

W. Michael Southern ◽

Anita E. Qualls ◽

Albino G. Schifino ◽

...

Keyword(s):

Skeletal Muscle ◽

Tibialis Anterior Muscle ◽

Metabolic Function ◽

Metabolic Dysfunction ◽

Cross Sectional ◽

Mouse Muscle ◽

Muscle Aging ◽

Age Related ◽

Skeletal Muscle Aging

AbstractThe accumulation of damaged mitochondria due to insufficient autophagy has been implicated in the pathophysiology of sarcopenia resulting in reduced contractile and metabolic function. Ulk1 is an autophagy-related kinase that initiates autophagosome assembly and may also play a role in autophagosome degradation (i.e., autophagy flux), but the contribution of Ulk1 to healthy muscle aging is unclear. We found that Ulk1 phosphorylation declines in both human and mouse muscle tissue with age, therefore the purpose of this study was to investigate the role of Ulk1-mediated autophagy in skeletal muscle aging. At age 22 months (80% survival rate), muscle contractile and metabolic function were assessed using electrophysiology in muscle specific Ulk1 knockout mice (MKO) and their littermate controls (LM). Specific peak-isometric torque of the ankle dorsiflexors (normalized by tibialis anterior muscle cross-sectional area) and specific force of the fast-twitch extensor digitorum longus muscles were reduced in MKO mice compared to LM mice (p<0.03). Permeabilized muscle fibers from MKO mice had greater mitochondrial content, yet lower mitochondrial oxygen consumption and greater reactive oxygen species production compared to fibers from LM mice (p≤ 0.04). Altered neuromuscular junction innervation patterns and changes in autophagosome numbers and/or flux in muscles from MKO may have contributed to decrements in contractile and metabolic function. Results from this study support an important role of Ulk1-mediated autophagy in skeletal muscle with age, reflecting Ulk1’s dual role in maintaining mitochondrial integrity through autophagosome assembly and degradation. A lifetime of insufficient Ulk-1-mediated autophagy in skeletal muscle exacerbates age-related contractile and metabolic dysfunction.

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Resistance training, sarcopenia, and the mitochondrial theory of aging

Applied Physiology Nutrition and Metabolism ◽

10.1139/h07-141 ◽

2008 ◽

Vol 33 (1) ◽

pp. 191-199 ◽

Cited By ~ 74

Author(s):

Adam P.W. Johnston ◽

Michael De Lisio ◽

Gianni Parise

Keyword(s):

Skeletal Muscle ◽

Resistance Training ◽

Resistance Exercise ◽

Strength Function ◽

Significant Loss ◽

Muscle Aging ◽

Age Related ◽

Dna Deletions ◽

Theory Of Aging ◽

Skeletal Muscle Aging

Skeletal muscle aging is associated with a significant loss of muscle mass, strength, function, and quality of life. In addition, the healthcare cost of aging and age-related disease is growing, and will continue to grow as a larger proportion of our population reaches retirement age and beyond. The mitochondrial theory of aging has been identified as a leading explanation of the aging process and describes a path leading to cellular senescence that includes electron transport chain deficiency, reactive oxygen species production, and the accumulation of mitochondrial DNA deletions and mutations. It is also quite clear that regular resistance exercise is a potent and effective countermeasure for skeletal muscle aging. In this review, we discuss age-related sarcopenia, the mitochondrial theory of aging, and how resistance exercise may directly affect key components of the mitochondrial theory. It is clear from the data discussed that regular resistance training can effectively disturb processes that contribute to the progression of aging as it pertains to the mitochondrial theory.

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Age-Related Increase in Lactate Dehydrogenase Activity in Skeletal Muscle Reduces Life Span in Drosophila

The Journals of Gerontology Series A ◽

10.1093/gerona/glab260 ◽

2021 ◽

Author(s):

Liam C Hunt ◽

Fabio Demontis

Keyword(s):

Skeletal Muscle ◽

Lactate Dehydrogenase ◽

Life Span ◽

Glycolytic Enzymes ◽

Lactate Dehydrogenase Activity ◽

Muscle Aging ◽

Age Related ◽

Extend Life Span ◽

Shorten Life Span ◽

Skeletal Muscle Aging

Abstract Metabolic adaptations occur with aging but the significance and causal roles of such changes are only partially known. In Drosophila, we find that skeletal muscle aging is paradoxically characterized by increased readouts of glycolysis (lactate, NADH/NAD+) but reduced expression of most glycolytic enzymes. This conundrum is explained by lactate dehydrogenase (LDH), an enzyme necessary for anaerobic glycolysis and whose expression increases with aging. Experimental Ldh overexpression in skeletal muscle of young flies increases glycolysis and shortens life span, suggesting that age-related increases in muscle LDH contribute to mortality. Similar results are also found with overexpression of other glycolytic enzymes (Pfrx/PFKFB, Pgi/GPI). Conversely, hypomorphic mutations in Ldh extend life span, whereas reduction in PFK, Pglym78/PGAM, Pgi/GPI, and Ald/ALDO levels shorten life span to various degrees, indicating that glycolysis needs to be tightly controlled for optimal aging. Altogether, these findings indicate a role for muscle LDH and glycolysis in aging.

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