Contraction-induced compromise of muscle function and, in the extreme, muscle damage has been linked to loss of Ca²⁺ homeostasis and resultant sustained elevation of intracellular Ca²⁺ ([Ca²⁺]_i). Against a background of in vitro approaches, a novel in vivo model permits investigation of the impact of different contraction types (e.g., isometric, ISO; eccentric, ECC) on [Ca²⁺]_i accumulation profiles. [Ca²⁺]_i elevation of ECC-contracted muscle is more rapid and greater in magnitude compared to ISO. Stretch-activated channels (SAC) are responsible, in large part, for this ECC contractions-induced [Ca²⁺]_i elevation. Transient Ca²⁺ accumulation in the cytosol incurs loss of force production, whereas continuous high levels of [Ca²⁺]_i, especially following ECC contractions, lead to muscle damage, including disrupted sarcomeres and membranes, and proceed, subsequently, to muscle regeneration via apoptosis and necrosis.