Muscle weakness associated with sarcopenia is a major contributor to reduced health span and quality of life in the elderly. However, the underlying mechanisms of muscle weakness in aging are not fully defined. We investigated the effect of oxidative stress and aging on specific molecular mechanisms involved in muscle force production in mice and skinned permeabilized single fibers in mice lacking the antioxidant enzyme CuZnSod (Sod1KO) and in aging (24-month-old) wild-type mice. Loss of muscle strength occurs in both models, potentially because of reduced membrane excitability with altered NKA signaling and RyR stability, decreased fiber Ca2+ sensitivity and suppressed SERCA activity via modification of the Cys674 residue, dysregulated SR and cytosolic Ca2+ homeostasis, and impaired mitochondrial Ca2+ buffering and respiration. Our results provide a better understanding of the specific impacts of aging and oxidative stress on mechanisms related to muscle weakness that may point to future interventions for countering muscle weakness.