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This Research Topic on muscle fatigue and muscle weakness presents the latest ideas, arguments, and evidence from investi-gations at the molecular level to macroscopic observations on whole animals including humans, in an effort to identify criti-cal factors underlying fatigue and weakness in health and disease. Skeletal muscles confer movement to the human body using vast amounts of energy provided through complex metabolic pathways such that whole body mobility and energy balance are largely dictated by muscle activity. Conversely, muscle func-tion reflects overall health status as exercise history and chronic conditions affect either or both muscle quality, including pro-tein and fat content, and muscle mass. In health, muscle fatigue is temporary and recovery occurs rapidly, and recreational or competitive athletes are always pursuing the next best fatigue “fix. ” However, after inactivity—whether due to lifestyle choices