Evidence for Altered Ca²⁺ Handling in Growth Associated Protein 43-Knockout Skeletal Muscle

Neuronal growth-associated protein 43 (GAP43) has crucial roles in the nervous system, and during development, regeneration after injury, and learning and memory. GAP43 is expressed in mouse skeletal muscle fibers and satellite cells, with suggested its involvement in intracellular Ca²⁺ handling. However, the physiological role of GAP43 in muscle remains unknown. Using a GAP43-knockout (GAP43^-/-) mouse, we have defined the role of GAP43 in skeletal muscle. GAP43^-/- mice showed low survival beyond weaning, reduced adult body weight, decreased muscle strength, and changed myofiber ultrastructure, with no significant differences in the expression of markers of satellite cell and myotube progression through the myogenic program. Thus, GAP43 expression is involved in timing of muscle maturation in-vivo. Intracellular Ca²⁺ measurements in-vitro in myotubes revealed GAP43 involvement in Ca²⁺ handling. In the absence of GAP43 expression, the spontaneous Ca²⁺ variations had greater amplitudes and higher frequency. In GAP43^-/^- myotubes, also the intracellular Ca²⁺ variations induced by the activation of dihydropyridine and ryanodine Ca²⁺ channels, resulted modified. These evidences suggested dysregulation of Ca²⁺ homeostasis. The emerging hypothesis indicates that GAP43 interacts with calmodulin to indirectly modulate the activities of dihydropyridine and ryanodine Ca²⁺ channels. This thus influences intracellular Ca²⁺ dynamics and its related intracellular patterns, from functional excitation-contraction coupling, to cell metabolism, and gene expression.