Human skeletal muscle demonstrates remarkable plasticity, adapting to numerous external stimuli including the habitual level of contractile loading. Accordingly, muscle function and exercise capacity encompass a broad spectrum, from inactive individuals with low levels of endurance and strength to elite athletes who produce prodigious performances underpinned by pleiotropic training-induced muscular adaptations. Our current understanding of the signal integration, interpretation, and output coordination of the cellular and molecular mechanisms that govern muscle plasticity across this continuum is incomplete. As such, training methods and their application to elite athletes largely rely on a "trial-and-error" approach, with the experience and practices of successful coaches and athletes often providing the bases for "post hoc" scientific enquiry and research. This review provides a synopsis of the morphological and functional changes along with the molecular mechanisms underlying exercise adaptation to endurance- and resistance-based training. These traits are placed in the context of innate genetic and interindividual differences in exercise capacity and performance, with special consideration given to aging athletes. Collectively, we provide a comprehensive overview of skeletal muscle plasticity in response to different modes of exercise and how such adaptations translate from "molecules to medals." CLINICAL HIGHLIGHTS 1) During human evolution, Homo sapiens emerged as mobile hunters and gatherers, dependent on the natural availability of food. However, today`s sedentary lifestyle and overabundant food availability place a major burden on our metabolic health and are strong drivers underpinning the dramatic rise in noncommunicable diseases. 2) A sedentary lifestyle, characterized by low maximal oxygen uptake (VO2max), unfavorable body composition, and low muscle strength, is an independent risk factor for many chronic diseases and a strong predictor of morbidity and mortality. 3) Despite marked interindividual differences in the response to standardized exercise training, regular physical activity lowers the risk of and confers therapeutic benefits for many noncommunicable diseases. 4) Endurance- and resistance-based exercise training protocols confer distinct clinical and health-related benefits and can prevent or reverse many lifestyle-induced metabolic diseases. 5) Clinical exercise tests based on established, validated physiological outcomes are essential for the diagnosis and subsequent monitoring of clinical conditions. 6) Investigations of elite human performance provide valuable insights into the molecular, cellular, tissue, and whole body adaptations to extreme metabolic loading. Identification of the mechanisms and pathways that limit exercise capacity may ultimately aid in the identification of novel therapeutic targets to be prescribed to patient populations.
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