Sarcopenia is an age-associated decline of skeletal muscle mass and function and is known to lead to frailty, cachexia, osteoporosis, metabolic syndromes, and death. Notwithstanding the increasing incidence of sarcopenia, the molecular and cellular mechanisms driving age-related sarcopenia are not completely understood. This article reviews current definitions of sarcopenia, its potential mechanisms, and effects of exercise on sarcopenia. The pathogenesis of age-related sarcopenia is multifactorial and includes myostatin, inflammatory cytokines, and mitochondria-derived problems. Especially, age-induced mitochondrial dysfunction triggers the production of reactive oxygen species (ROS) by mitochondria, impedes mitochondrial dynamics, interrupts mitophagy, and leads to mitochondria-mediated apoptosis. Aerobic exercise provides at least a partial solution to sarcopenia as it ameliorates mitochondria-derived problems, and resistance exercise strengthens muscle mass and function. Furthermore, combinations of these exercise types provide the benefits of both. Collectively, this review summarizes potential mechanisms of age-related sarcopenia and emphasizes the use of exercise as a therapeutic strategy, suggesting that combined exercise provides the most beneficial means of combating age-related sarcopenia.

The aging process in skeletal muscle is characterized by a loss of myocytes and reduction in cross-sectional area of the remaining myocytes, particularly in Type II (fast-twitch) muscle fibers. In multinucleated skeletal muscle, apoptosis may contribute to both fiber atrophy and loss of muscle fibers. Recent evidence suggests that the mitochondrial Bcl-2 family pathway may be a target of aging. Here the authors demonstrated that aging increased DNA fragmentation, cleaved caspase-3, and pro-apoptotic Bax in rat skeletal muscle. Twelve weeks of treadmill exercise training increased anti-apoptotic Bcl-2, while markedly reducing DNA fragmentation, and cleaved caspase-3, Bax, and Bax/Bcl-2 ratio in the white gastrocnemius and soleus muscles of old rats. Upstream anti-apoptotic NF-kappaB activity decreased in aging skeletal muscle, and increased with exercise training. Regulation of NF-kappaB activity with aging and exercise was not related to changes in NF-kappaB subunit protein levels. Instead, changes in post-translational activation of NF-kappaB occurred as a function of altered phosphorylation of IkappaB. These results indicate that treadmill exercise training attenuates fiber atrophy and pro-apoptotic signaling in aging skeletal muscle.

Statins, the widely prescribed cholesterol-lowering drugs for the treatment of cardiovascular disease, cause adverse skeletal muscle side effects ranging from fatigue to fatal rhabdomyolysis. The purpose of this study was to determine the effects of simvastatin on mitochondrial respiration, oxidative stress, and cell death in differentiated primary human skeletal muscle cells (i.e. myotubes). Simvastatin induced a dose dependent decrease in viability of proliferating and differentiating primary human muscle precursor cells, and a similar dose-dependent effect was noted in differentiated myoblasts and myotubes. Additionally, there were decreases in myotube number and size following 48 h of simvastatin treatment (5 µM). In permeabilized myotubes, maximal ADP-stimulated oxygen consumption, supported by palmitoyl-carnitine + malate (PCM, complex I and II substrates) and glutamate + malate (GM, complex I substrates), was 32–37% lower (P<0.05) in simvastatin treated (5 µM) vs. control myotubes, providing evidence of impaired respiration at complex I. Mitochondrial superoxide and hydrogen peroxide generation were significantly greater in the simvastatin treated human skeletal myotube cultures compared to control. In addition, simvastatin markedly increased protein levels of Bax (pro-apoptotic, +53%) and Bcl-2 (anti-apoptotic, +100%, P<0.05), mitochondrial PTP opening (+44%, P<0.05), and TUNEL-positive nuclei in human skeletal myotubes, demonstrating up-regulation of mitochondrial-mediated myonuclear apoptotic mechanisms. These data demonstrate that simvastatin induces myotube atrophy and cell loss associated with impaired ADP-stimulated maximal mitochondrial respiratory capacity, mitochondrial oxidative stress, and apoptosis in primary human skeletal myotubes, suggesting mitochondrial dysfunction may underlie human statin-induced myopathy.

Seeding a monolayer of primary human endothelial cells on the surface of a polymerized three-dimensional collagen matrix in the presence of pro-angiogenic stimuli allows manipulation and analysis of rapid sprouting responses. This protocol is useful for elucidating incompletely defined intracellular mechanisms downstream of pro-angiogenic factors that regulate sprout formation and initiation, and can also be used to test the efficacy of pro-and anti-angiogenic compounds. We present protocols to culture endothelial cells, prepare three-dimensional collagen matrices and quantify and image rapid endothelial sprouting responses (24 h). This protocol can be carried out using either type I or type II collagen matrices with primary endothelial cells isolated from macrovascular and microvascular sources of varying species.

Ursolic acid (UA) is a natural triterpene compound found in various fruits and vegetables. There is a growing interest in UA because of its beneficial effects, which include anti-inflammatory, anti-oxidant, anti-apoptotic, and anti-carcinogenic effects. It exerts these effects in various tissues and organs: by suppressing nuclear factor-kappa B signaling in cancer cells, improving insulin signaling in adipose tissues, reducing the expression of markers of cardiac damage in the heart, decreasing inflammation and increasing the level of anti-oxidants in the brain, reducing apoptotic signaling and the level of oxidants in the liver, and reducing atrophy and increasing the expression levels of adenosine monophosphate-activated protein kinase and irisin in skeletal muscles. Moreover, UA can be used as an alternative medicine for the treatment and prevention of cancer, obesity/diabetes, cardiovascular disease, brain disease, liver disease, and muscle wasting (sarcopenia). In this review, we have summarized recent data on the beneficial effects and possible uses of UA in health and disease managements.