Exercise interventions delivered significant muscle strength preservation during hospitalization (effect size 0.60) and maintained muscle mass during both bed rest and spaceflight conditions across 1754 participants. Resistance training emerged as particularly effective, with therapeutic interventions showing weaker benefits than preventive approaches. The research landscape around disuse atrophy has historically focused on single conditions, but this comprehensive analysis reveals exercise effectiveness varies dramatically by context. Hospitalization scenarios showed robust benefits, while spaceflight countermeasures demonstrated surprisingly modest effects despite decades of research investment. For aging adults, these findings underscore exercise's critical role in preventing the muscle wasting that accelerates during illness or prolonged inactivity. The distinction between preventive versus therapeutic timing carries practical implications—maintaining fitness before health crises appears more effective than recovery efforts afterward. However, the high heterogeneity between studies (I² = 76%) and reliance on surrogate endpoints rather than functional outcomes limits definitive clinical guidance. This represents confirmatory rather than paradigm-shifting evidence, validating exercise prescriptions while highlighting the complexity of translating controlled interventions to real-world medical settings where compliance and implementation vary significantly.