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

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.

scholarly journals Lifelong Ulk1-Mediated Autophagy Deficiency in Muscle Induces Mitochondrial Dysfunction and Contractile Weakness

2021 ◽  
Vol 22 (4) ◽  
pp. 1937
Author(s):  
Anna S. Nichenko ◽  
Jacob R. Sorensen ◽  
W. Michael Southern ◽  
Anita E. Qualls ◽  
Albino G. Schifino ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Tibialis Anterior Muscle ◽  
Autophagy Flux ◽  
Cross Sectional ◽  
Muscle Aging ◽  
Skeletal Muscle Aging ◽  
Species Production ◽  
Fast Twitch ◽  
Muscle Cross Sectional Area

The accumulation of damaged mitochondria due to insufficient autophagy has been implicated in the pathophysiology of skeletal muscle aging. 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. 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 was 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). Alterations in neuromuscular junction innervation patterns as well as changes to autophagosome assembly and flux were explored as possible contributors to the pathological features in Ulk1 deficiency. Of primary interest, we found that Ulk1 phosphorylation (activation) to total Ulk1 protein content was reduced in older muscles compared to young muscles from both human and mouse, which may contribute to decreased autophagy flux and an accumulation of dysfunctional mitochondria. Results from this study support the role of Ulk1-mediated autophagy in aging skeletal muscle, reflecting Ulk1′s dual role in maintaining mitochondrial integrity through autophagosome assembly and degradation.

scholarly journals Role of Age-Related Mitochondrial Dysfunction in Sarcopenia

2020 ◽  
Vol 21 (15) ◽  
pp. 5236 ◽  
Author(s):  
Evelyn Ferri ◽  
Emanuele Marzetti ◽  
Riccardo Calvani ◽  
Anna Picca ◽  
Matteo Cesari ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Cellular Senescence ◽  
Significant Loss ◽  
Muscle Aging ◽  
Age Related ◽  
Mitochondrial Functions ◽  
Health Quality ◽  
Skeletal Muscle Aging ◽  
And Function

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.

scholarly journals Role of miRNAs in skeletal muscle aging

2018 ◽  
Vol Volume 13 ◽  
pp. 2407-2419 ◽  
Author(s):  
Yan Zheng ◽  
Jian Kong ◽  
Qun Li ◽  
Yan Wang ◽  
Jie Li
Keyword(s):  
Skeletal Muscle ◽  
Muscle Aging ◽  
Skeletal Muscle Aging

scholarly journals THE ROLE OF MITOCHONDRIAL ENERGETICS IN CARDIAC AND SKELETAL MUSCLE AGING

2018 ◽  
Vol 2 (suppl_1) ◽  
pp. 348-348
Author(s):  
P Rabinovitch ◽  
D J Marcinek
Keyword(s):  
Skeletal Muscle ◽  
Muscle Aging ◽  
Skeletal Muscle Aging

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

2019 ◽  
pp. 157-200 ◽  
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

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

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.

scholarly journals Biological Aspects of Selected Myokines in Skeletal Muscle: Focus on Aging

2021 ◽  
Vol 22 (16) ◽  
pp. 8520
Author(s):  
Rosa Mancinelli ◽  
Franco Checcaglini ◽  
Francesco Coscia ◽  
Paola Gigliotti ◽  
Stefania Fulle ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Potential Role ◽  
Immunological Response ◽  
Active Lifestyle ◽  
Muscle Aging ◽  
Biological Aspects ◽  
Skeletal Muscle Aging ◽  
Cellular Components ◽  
Proteins And Peptides

In the last decade, clear evidence has emerged that the cellular components of skeletal muscle are important sites for the release of proteins and peptides called “myokines”, suggesting that skeletal muscle plays the role of a secretory organ. After their secretion by muscles, these factors serve many biological functions, including the exertion of complex autocrine, paracrine and/or endocrine effects. In sum, myokines affect complex multi-organ processes, such as skeletal muscle trophism, metabolism, angiogenesis and immunological response to different physiological (physical activity, aging, etc.) or pathological states (cachexia, dysmetabolic conditions, chronic inflammation, etc.). The aim of this review is to describe in detail a number of myokines that are, to varying degrees, involved in skeletal muscle aging processes and belong to the group of proteins present in the functional environment surrounding the muscle cell known as the “Niche”. The particular myokines described are those that, acting both from within the cell and in an autocrine manner, have a defined relationship with the modulation of oxidative stress in muscle cells (mature or stem) involved in the regulatory (metabolic or regenerative) processes of muscle aging. Myostatin, IGF-1, NGF, S100 and irisin are examples of specific myokines that have peculiar features in their mechanisms of action. In particular, the potential role of one of the most recently characterized myokines—irisin, directly linked to an active lifestyle—in reducing if not reversing senescence-induced oxidative damage is discussed in terms of its possible application as an agent able to counteract the deleterious effects of muscle aging.

Skeletal muscle aging

2007 ◽  
Vol 17 (1) ◽  
pp. 13-23 ◽  
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.

scholarly journals Advanced Glycation End-Products in Skeletal Muscle Aging

2021 ◽  
Vol 8 (11) ◽  
pp. 168
Author(s):  
Lucas C. Olson ◽  
James T. Redden ◽  
Zvi Schwartz ◽  
David J. Cohen ◽  
Michael J. McClure
Keyword(s):  
Skeletal Muscle ◽  
Advanced Glycation End Products ◽  
Future Research ◽  
Cross Linking ◽  
Advanced Glycation ◽  
Muscle Aging ◽  
Glycation End Products ◽  
End Products ◽  
Skeletal Muscle Aging

Advanced age causes skeletal muscle to undergo deleterious changes including muscle atrophy, fast-to-slow muscle fiber transition, and an increase in collagenous material that culminates in the age-dependent muscle wasting disease known as sarcopenia. Advanced glycation end-products (AGEs) non-enzymatically accumulate on the muscular collagens in old age via the Maillard reaction, potentiating the accumulation of intramuscular collagen and stiffening the microenvironment through collagen cross-linking. This review contextualizes known aspects of skeletal muscle extracellular matrix (ECM) aging, especially the role of collagens and AGE cross-linking, and underpins the motor nerve’s role in this aging process. Specific directions for future research are also discussed, with the understudied role of AGEs in skeletal muscle aging highlighted. Despite more than a half century of research, the role that intramuscular collagen aggregation and cross-linking plays in sarcopenia is well accepted yet not well integrated with current knowledge of AGE’s effects on muscle physiology. Furthermore, the possible impact that motor nerve aging has on intramuscular cross-linking and muscular AGE levels is posited.

Resistance training, sarcopenia, and the mitochondrial theory of aging

2008 ◽  
Vol 33 (1) ◽  
pp. 191-199 ◽  
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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