Molecular Basis of Exercise-Induced Skeletal Muscle Mitochondrial Biogenesis: Historical Advances, Current Knowledge, and Future Challenges

Abstract

We provide an overview of groundbreaking studies that laid the foundation for our current understanding of exercise-induced mitochondrial biogenesis and its contribution to human skeletal muscle fitness. We highlight the mechanisms by which skeletal muscle responds to the acute perturbations in cellular energy homeostasis evoked by a single bout of endurancebased exercise and the adaptations resulting from the repeated demands of exercise training that ultimately promote mitochondrial biogenesis through hormetic feedback loops. Despite intense research efforts to elucidate the cellular mechanisms underpinning mitochondrial biogenesis in skeletal muscle, translating this basic knowledge into improved metabolic health at the population level remains a future challenge. E xercise represents a major challenge to multiple whole-body homeostatic functions. In an effort to overcome this challenge, numerous responses take place at the cellular and systemic levels that operate to blunt the homeostatic threats generated by exercise-induced increases in muscle energy turnover and oxygen demand . The capacity of skeletal muscle to adapt to repeated bouts of activity such that physical capacity is enhanced is termed exercise training. When considering endurance-based exercise (e.g., sustained activities that are .10 min duration and performed at 60% -90% of maximal oxygen uptake [VO 2max ] including sprint-interval training), the goals of such exercise are to induce an array of physiological and metabolic adaptations that enable an individual to increase the rate of energy production from both aerobic pathways, maintain tighter metabolic control (i.e., match adenosine triphosphate (ATP) production with ATP hydrolysis), minimize cellular perturbations, increase efficiency of motion, and improve the capacity of the trained musculature to resist

An appraisal of the SD IR as an estimate of true individual differences in training responsiveness in parallel‐arm exercise randomized controlled trials

“…Additionally, although acute exercise studies involve non‐blinded participants, these studies are relatively short (e.g. measurements collected at baseline and three hours–postacute exercise (Egan and Zierath, ; Perry and Hawley, )) and may not provide enough time for behavioral–environmental differences (i.e., factors contributing to V ΔWS) to emerge between EX and CON. To our knowledge, only one acute exercise study has utilized the SD IR (Bonafiglia et al, ), highlighting acute exercise as a feasible model for exploring the existence and magnitude of V ΔTRUE.…”

Transplantation of Muscle Stem Cell Mitochondria Rejuvenates the Bioenergetic Function of Dystrophic Muscle

“…The beneficial effects of endurance exercise training on skeletal muscle mitochondrial biogenesis and mitochondrial function have been well characterized (Baar et al, 2002;Dohm et al, 1973;Hood, 2009;Perry and Hawley, 2018). Likewise, endurance exercise has been shown to promote myogenesis and myonuclear accretion (Hawke, 2005;Shefer et al, 2010;Smith et al, 2001).…”

Hormones, Metabolism and the Benefits of Exercise

“…The goals of endurance exercise training are to induce an array of physiological and metabolic adaptations that enable an individual to increase the rate of energy production from both aerobic and oxygen-independent pathways, maintain tighter metabolic control (i.e., match ATP production with ATP hydrolysis), minimize cellular perturbations, increase efficiency of motion, and improve the capacity of the trained musculature to resist fatigue (Hawley 2002). The mechanisms and metabolic signals by which active muscle senses homeostatic perturbations and then translates them into improved function has been a topic of intense research for several decades (for review, see Perry and Hawley 2017). It is now accepted that a variety of cellular disruptions takes place at the onset of exercise, including (but not limited to) increased cytoplasmic free [Ca 2+ ], increased free AMP (AMPf) and an increased ADP/ATP ratio, reduced creatine phosphate and glycogen levels, increased FA concentrations and reactive oxygen/nitrogen species (ROS/RNS), acidosis and altered redox state, including [NAD/NADH] Perry and Hawley 2017).…”

“…The mechanisms and metabolic signals by which active muscle senses homeostatic perturbations and then translates them into improved function has been a topic of intense research for several decades (for review, see Perry and Hawley 2017). It is now accepted that a variety of cellular disruptions takes place at the onset of exercise, including (but not limited to) increased cytoplasmic free [Ca 2+ ], increased free AMP (AMPf) and an increased ADP/ATP ratio, reduced creatine phosphate and glycogen levels, increased FA concentrations and reactive oxygen/nitrogen species (ROS/RNS), acidosis and altered redox state, including [NAD/NADH] Perry and Hawley 2017). Within the context of metabolic homeostasis, an array of regulatory networks is stimulated that sustain rates of ATP synthesis over time through the activation of rate-limiting enzymes controlling carbohydrate and fat catabolism.…”

“…A key component of improved "muscle fitness" following exercise training is biogenesis of mitochondria in skeletal muscle. A comprehensive discussion of this topic is beyond the scope of this chapter and the reader is referred to recent reviews (Hood et al 2016;Perry and Hawley 2017). In brief, the molecular bases of skeletal muscle adaptations to an endurance exercise stimulus requires increased expression and/or activity of key mitochondrial proteins mediated by an array of intra-cellular signaling events, pre-and post-transcriptional processes, regulation of translation and protein expression, and modulation of protein (enzyme) activities and/or intracellular localization.…”