Role of Age-Related Mitochondrial Dysfunction in Sarcopenia

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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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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Role of miRNAs in skeletal muscle aging

Clinical Interventions in Aging ◽

10.2147/cia.s169202 ◽

2018 ◽

Vol Volume 13 ◽

pp. 2407-2419 ◽

Cited By ~ 5

Author(s):

Yan Zheng ◽

Jian Kong ◽

Qun Li ◽

Yan Wang ◽

Jie Li

Keyword(s):

Skeletal Muscle ◽

Muscle Aging ◽

Skeletal Muscle Aging

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THE ROLE OF MITOCHONDRIAL ENERGETICS IN CARDIAC AND SKELETAL MUSCLE AGING

Innovation in Aging ◽

10.1093/geroni/igy023.1278 ◽

2018 ◽

Vol 2 (suppl_1) ◽

pp. 348-348

Author(s):

P Rabinovitch ◽

D J Marcinek

Keyword(s):

Skeletal Muscle ◽

Muscle Aging ◽

Skeletal Muscle Aging

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Healthy skeletal muscle aging: The role of satellite cells, somatic mutations and exercise

International Review of Cell and Molecular Biology ◽

10.1016/bs.ircmb.2019.03.003 ◽

2019 ◽

pp. 157-200 ◽

Cited By ~ 2

Author(s):

Irene Franco ◽

Rodrigo Fernandez-Gonzalo ◽

Peter Vrtačnik ◽

Tommy R. Lundberg ◽

Maria Eriksson ◽

...

Keyword(s):

Skeletal Muscle ◽

Satellite Cells ◽

Somatic Mutations ◽

Muscle Aging ◽

Skeletal Muscle Aging

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An investigation of p53 in skeletal muscle aging

Journal of Applied Physiology ◽

10.1152/japplphysiol.00363.2019 ◽

2019 ◽

Vol 127 (4) ◽

pp. 1075-1084 ◽

Cited By ~ 2

Author(s):

Scott M. Ebert ◽

Jason M. Dierdorff ◽

David K. Meyerholz ◽

Steven A. Bullard ◽

Asma Al-Zougbi ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Muscle Fibers ◽

Skeletal Muscle Atrophy ◽

P53 Expression ◽

Skeletal Muscle Fibers ◽

Age Related ◽

Skeletal Muscle Aging ◽

And Function

Age-related skeletal muscle atrophy is a very common and serious condition that remains poorly understood at the molecular level. Several lines of evidence have suggested that the tumor suppressor p53 may play a central, causative role in skeletal muscle aging, whereas other, apparently contradictory lines of evidence have suggested that p53 may be critical for normal skeletal muscle function. To help address these issues, we performed an aging study in male muscle-specific p53-knockout mice (p53 mKO mice), which have a lifelong absence of p53 expression in skeletal muscle fibers. We found that the absence of p53 expression in skeletal muscle fibers had no apparent deleterious or beneficial effects on skeletal muscle mass or function under basal conditions up to 6 mo of age, when mice are fully grown and exhibit peak muscle mass and function. Furthermore, at 22 and 25 mo of age, when age-related muscle weakness and atrophy are clearly evident in mice, p53 mKO mice demonstrated no improvement or worsening of skeletal muscle mass or function relative to littermate control mice. At advanced ages, p53 mKO mice began to die prematurely and had an increased incidence of osteosarcoma, precluding analyses of muscle mass and function in very old p53 mKO mice. In light of these results, we conclude that p53 expression in skeletal muscle fibers has minimal if any direct, cell autonomous effect on basal or age-related changes in skeletal muscle mass and function up to at least 22 mo of age. NEW & NOTEWORTHY Previous studies implicated the transcriptional regulator p53 as a potential mediator of age-related skeletal muscle weakness and atrophy. We tested this hypothesis by investigating the effect of aging in muscle-specific p53-knockout mice. Our results strongly suggest that p53 activity within skeletal muscle fibers is not required for age-related skeletal muscle atrophy or weakness.

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MICU3 regulates mitochondrial Ca2+-dependent antioxidant response in skeletal muscle aging

Cell Death and Disease ◽

10.1038/s41419-021-04400-5 ◽

2021 ◽

Vol 12 (12) ◽

Author(s):

Yun-Fei Yang ◽

Wu Yang ◽

Zhi-Yin Liao ◽

Yong-Xin Wu ◽

Zhen Fan ◽

...

Keyword(s):

Oxidative Stress ◽

Skeletal Muscle ◽

Muscle Mass ◽

Skeletal Muscle Mass ◽

Calcium Uptake ◽

Mitochondrial Calcium ◽

Muscle Aging ◽

Skeletal Muscle Aging ◽

And Function ◽

Mitochondrial Calcium Uptake

AbstractAge-related loss of skeletal muscle mass and function, termed sarcopenia, could impair the quality of life in the elderly. The mechanisms involved in skeletal muscle aging are intricate and largely unknown. However, more and more evidence demonstrated that mitochondrial dysfunction and apoptosis also play an important role in skeletal muscle aging. Recent studies have shown that mitochondrial calcium uniporter (MCU)-mediated mitochondrial calcium affects skeletal muscle mass and function by affecting mitochondrial function. During aging, we observed downregulated expression of mitochondrial calcium uptake family member3 (MICU3) in skeletal muscle, a regulator of MCU, which resulted in a significant reduction in mitochondrial calcium uptake. However, the role of MICU3 in skeletal muscle aging remains poorly understood. Therefore, we investigated the effect of MICU3 on the skeletal muscle of aged mice and senescent C2C12 cells induced by d-gal. Downregulation of MICU3 was associated with decreased myogenesis but increased oxidative stress and apoptosis. Reconstitution of MICU3 enhanced antioxidants, prevented the accumulation of mitochondrial ROS, decreased apoptosis, and increased myogenesis. These findings indicate that MICU3 might promote mitochondrial Ca2+ homeostasis and function, attenuate oxidative stress and apoptosis, and restore skeletal muscle mass and function. Therefore, MICU3 may be a potential therapeutic target in skeletal muscle aging.

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Molecular Basis for the Therapeutic Effects of Exercise on Mitochondrial Defects

Frontiers in Physiology ◽

10.3389/fphys.2020.615038 ◽

2021 ◽

Vol 11 ◽

Author(s):

Jonathan M. Memme ◽

David A. Hood

Keyword(s):

Skeletal Muscle ◽

Mitochondrial Dysfunction ◽

Muscle Pathology ◽

Therapeutic Effects ◽

Atp Production ◽

Muscle Aging ◽

Mitochondrial Defects ◽

Aging Muscle ◽

Skeletal Muscle Aging ◽

And Function

Mitochondrial dysfunction is common to many organ system disorders, including skeletal muscle. Aging muscle and diseases of muscle are often accompanied by defective mitochondrial ATP production. This manuscript will focus on the pre-clinical evidence supporting the use of regular exercise to improve defective mitochondrial metabolism and function in skeletal muscle, through the stimulation of mitochondrial turnover. Examples from aging muscle, muscle-specific mutations and cancer cachexia will be discussed. We will also examine the effects of exercise on the important mitochondrial regulators PGC-1α, and Parkin, and summarize the effects of exercise to reverse mitochondrial dysfunction (e.g., ROS production, apoptotic susceptibility, cardiolipin synthesis) in muscle pathology. This paper will illustrate the breadth and benefits of exercise to serve as “mitochondrial medicine” with age and disease.

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