The pleiotropic effect of physical exercise on mitochondrial dynamics in aging skeletal muscle

Abstract

Decline in human muscle mass and strength (sarcopenia) is one of the principal hallmarks of the aging process. Regular physical exercise and training programs are certain powerful stimuli to attenuate the physiological skeletal muscle alterations occurring during aging and contribute to promote health and well-being. Although the series of events that led to these muscle adaptations are poorly understood, the mechanisms that regulate these processes involve the "quality" of skeletal muscle mitochondria. Aerobic/endurance exercise helps to maintain and improve cardiovascular fitness and respiratory function, whereas strength/resistance-exercise programs increase muscle strength, power development, and function. Due to the different effect of both exercises in improving mitochondrial content and quality, in terms of biogenesis, dynamics, turnover, and genotype, combined physical activity programs should be individually prescribed to maximize the antiaging effects of exercise.

Figure 1

Effect of physical exercise and major signalling pathways activated on mitochondrial “quality” in aging skeletal muscle. Mitochondria represent the privileged site of ROS production. ROS may either act as signalling molecules, inducing a prosurvival response with positive muscle adaptation, or cause damage to cell components and sarcopenia. Low levels of ROS generated by skeletal muscle contraction activate a mitochondrial response that ameliorate the “quality” of skeletal muscle mitochondria cells at different molecular levels: (i) biogenesis through the action of the key regulators PGC-1α, NRF-1/2, T-FAM, and mTFB-1/2; (ii) dynamics by the mitochondrial remodeling GTPase proteins such as mitofusin-1/2 and OPA-1 for fusion and DRP-1 and FIS-1 for fission; (iii) turnover of damaged mitochondria by mitophagy through PINK-1, PARKIN, ATROGINS, and BNIP-3; and (iv) quality control by degradation of misfolded proteins or again portion of damaged mitochondria by the proteolytic system with chaperones and proteases. Slight ROS accumulation also promotes the phosphorylation state of many proteins involved in the muscle signalling responses. Moreover, low levels of ROS induced by RT play an important role in inducing upregulation of growth factors such as IGF-I. The expression of this muscle hormone has beneficial effects in muscle protein balance, muscle adaptation, and increasing muscle mass; neural activation; and number of activated satellite cells and contributes to the development of an oxidant-resistant phenotype, therefore preventing oxidative damage and chronic diseases. Moreover, the incorporation of satellite cell-derived mitochondria explains the increase in wild-type mtDNA known as “gene-shifting.” Thus, low levels of ROS elicit positive effects on muscle physiological responses. Moreover, antioxidant enzymes will function as back regulators of intracellular low ROS levels. By contrast, high levels of ROS cause functional oxidative damages of proteins, lipids, nucleic acids, and cell components and promote signalling cascades for mitoptosis or apoptosis. For these reasons high levels of ROS act as worsening factors in muscle atrophy, sarcopenia, and aging-related muscle diseases. Uptake of calcium by mitochondria, together with ROS, control mitochondrial quality responses in skeletal muscle cells and it is tightly regulated by sarcomeric localization and muscle chronic contraction. It occurs at calcium release unit (CRU) mitochondrion contacts where microdomains of high calcium concentration are present. RT: resistance training; CRUs: calcium release units; mtDNA: mitochondrial DNA; ET: endurance training; ROS: reactive oxygen species.