Calcium Ion in Skeletal Muscle: Its Crucial Role for Muscle Function, Plasticity, and Disease

Abstract

Mammalian skeletal muscle shows an enormous variability in its functional features such as rate of force production, resistance to fatigue, and energy metabolism, with a wide spectrum from slow aerobic to fast anaerobic physiology. In addition, skeletal muscle exhibits high plasticity that is based on the potential of the muscle fibers to undergo changes of their cytoarchitecture and composition of specific muscle protein isoforms. Adaptive changes of the muscle fibers occur in response to a variety of stimuli such as, e.g., growth and differentition factors, hormones, nerve signals, or exercise. Additionally, the muscle fibers are arranged in compartments that often function as largely independent muscular subunits. All muscle fibers use Ca²⁺ as their main regulatory and signaling molecule. Therefore, contractile properties of muscle fibers are dependent on the variable expression of proteins involved in Ca²⁺ signaling and handling. Molecular diversity of the main proteins in the Ca²⁺ signaling apparatus (the calcium cycle) largely determines the contraction and relaxation properties of a muscle fiber. The Ca²⁺ signaling apparatus includes1) the ryanodine receptor that is the sarcoplasmic reticulum Ca²⁺ release channel, 2) the troponin protein complex that mediates the Ca²⁺ effect to the myofibrillar structures leading to contraction, 3) the Ca²⁺pump responsible for Ca²⁺ reuptake into the sarcoplasmic reticulum, and 4) calsequestrin, the Ca²⁺storage protein in the sarcoplasmic reticulum. In addition, a multitude of Ca²⁺-binding proteins is present in muscle tissue including parvalbumin, calmodulin, S100 proteins, annexins, sorcin, myosin light chains, β-actinin, calcineurin, and calpain. These Ca²⁺-binding proteins may either exert an important role in Ca²⁺-triggered muscle contraction under certain conditions or modulate other muscle activities such as protein metabolism, differentiation, and growth. Recently, several Ca²⁺signaling and handling molecules have been shown to be altered in muscle diseases. Functional alterations of Ca²⁺ handling seem to be responsible for the pathophysiological conditions seen in dystrophinopathies, Brody's disease, and malignant hyperthermia. These also underline the importance of the affected molecules for correct muscle performance.