Ca²⁺ sparks as a plastic signal for skeletal muscle health, aging, and dystrophy

Ca²⁺ sparks are the elementary units of intracellular Ca ²⁺ signaling in striated muscle cells revealed as localized Ca ²⁺ release events from sarcoplasmic reticulum (SR) by confocal microscopy. While Ca²⁺ sparks are well defined in cardiac muscle, there has been a general belief that these localized Ca²⁺ release events are rare in intact adult mammalian skeletal muscle. Several laboratories determined that Ca²⁺ sparks in mammalian skeletal muscle could only be observed in large numbers when the sarcolemmal membranes are permeabilized or the SR Ca²⁺ content is artificially manipulated, thus the cellular and molecular mechanisms underlying the regulation of Ca²⁺ sparks in skeletal muscle remain largely unexplored. Recently, we discovered that membrane deformation generated by osmotic stress induced a robust Ca²⁺ spark response confined in close spatial proximity to the sarcolemmal membrane in intact mouse muscle fibers. In addition to Ca²⁺ sparks, prolonged Ca²⁺ transients, termed Ca²⁺ bursts, are also identified in intact skeletal muscle. These induced Ca²⁺ release events are reversible and repeatable, revealing a plastic nature in young muscle fibers. In contrast, induced Ca²⁺ sparks in aged muscle are transient and cannot be re-stimulated. Dystrophic muscle fibers display uncontrolled Ca ²⁺ sparks, where osmotic stress-induced Ca²⁺ sparks are not reversible and they are no longer spatially restricted to the sarcolemmal membrane. An understanding of the mechanisms that underlie generation of osmotic stress-induced Ca²⁺ sparks in skeletal muscle, and how these mechanisms are altered in pathology, will contribute to our understanding of the regulation of Ca²⁺ homeo-stasis in muscle physiology and pathophysiology.