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What Is the Importance of Calcium in Muscle Contraction

The functional units of skeletal muscle are muscle fibers, long, multinucleated cylindrical cells. They differ significantly in morphological, biochemical and physiological properties. In each muscle, different types of fiber can be distinguished. The composition of the fibers, which varies from one muscle to another, is the basis of the known structural and functional muscle diversity. Fibers can change their properties in response to a variety of stimuli that lead to muscle plasticity. All muscles use Ca2+ as the most important regulatory and signaling molecule. Therefore, muscle plasticity is closely related to and strongly dependent on the Ca2+ manipulation system. A search for mutations in ATP2A1, the gene that codes for SERCA1, revealed genetic heterogeneity in Brody`s disease. Zhang et al. (569) were unable to find a mutation in the ATP2A1 gene in three patients. Odermatt et al.

(377) identified three different mutations in two families associated with autosomal recessive heredity. One mutation occurred at the splice donor site of intron 3, and the other two mutations led to preterm stop codons in ATP2A1 (377). The C592T mutation causes a change from the CCA codon (Arg-198) to TGA (Stop) and shortens SERCA1 to position 197 (Fig. 11). Based on the current model of structure-function relationships of SERCA-type Ca2+ pumps (321), the resulting protein does not have the nucleotide binding and Ca2+ binding domains and is therefore ineffective. The same result, the absence of nucleotide and Ca2+ binding domains, is predicted for splice mutation. The third nonsense mutation detected, C2025A, disrupts the Ca2+ binding domain of the truncated protein and leaves the nucleotide binding site functional (321,377). Thus, all three mutations are likely to lead to inactive SERCA1 proteins in vivo (Fig. 11). From these data, the surprising consequence stems from the fact that the muscles of those affected completely lack functional SERCA1 and that type II muscle fibers function quite well without the rapidly contracting isoform of the SR Ca2+ pump.

The nature of possible compensation mechanisms has not yet been clarified. Some interesting data regarding the pathological mechanism of dystrophy were obtained from comparisons of the specificity of the fiber type of muscle lesions. In human DMD, rapidly contracting glycolytic IIB (IIX) muscle fibers were found to be preferentially affected (128, 546). The authors suggested that the burst stimulation model and the high force production of Type IIB fibers (IIX) are less compatible with dystrophin deficiency. A similar result was found in the mdx muscle. Here, the authors described that small-caliber fibers tolerate dystrophin deficiency better than larger IIB (IIX) fibers (241). The observation that extraocular muscles are not affected in DMD (252) is consistent with the observations discussed. The fibers of the extraocular muscles are characterized by small diameters and a very rapid resumption of SR after activation.

The control of contraction and relaxation by ca2+ in different types of muscles is achieved through three main mechanisms. The first activation mechanism that has been discovered and best described is the troponin-tropomyosin system, which is associated with actin filaments. It is limited to skeletal and cardiac muscles. In the second mechanism, which occurs in the smooth muscles of vertebrates, Ca2 + with calmodulin (CaM) activates the light chain kinase of myosin, which initiates muscle contraction (by phosphorylation of the light chains of myosin). The third mechanism is the direct binding of Ca2+ to myosin, which regulates the contraction in the muscles of certain invertebrates such as scallops. This system depends on the presence of myosin regulating light chains. In addition to calcium gates, heart muscle cells are also equipped with other gates responsible for the movements of other particles entering and leaving the cell, such as sodium, potassium, and chloride. Recently, scientists have discovered that calcium can regulate the activity of these other gates, making them easier or harder to open, highlighting the great responsibility of calcium in heart muscle cells [2]. Since membrane lesions are of limited size at the beginning of the necrotic process and Ca2+ is rapidly bound by target proteins, the early consequences of Ca2+ influx will likely be limited to the sub-sarmatous space of muscle fibers. A key factor may be the increase in calpain activity (see sect.ivE, Calpains). Possible substrates of calphenes are membrane cytoskeleton, Ca2+ plasma membrane ATPase and ion channel proteins. The Ca2+ pump located in the plasma diaphragm is a preferred substrate for calpain in erythrocytes (439), and when attacked in dystrophin-deficient muscles, this calphenine action would interfere with an important extrusion pathway in addition to excess Ca2+ inflow.

Another route of Ca2+ influx, in addition to that mediated by membrane lesions, has been demonstrated by Turner et al. (524). They showed that proteolytic cleavage of ca2+ channels of the plasma membrane can lead to an increase in openings in these channels (524). This could mean a positive feedback loop of Ca2+ influx, Ca2+ dependent proteolysis and increased Ca2+ influx (Fig. 14). Thus, dystrophinopathies are mainly diseases of sarkolemma. This hypothesis is based on the first reports of accumulation of Ca2+ in DMD muscle fibers. Red alizarin staining, a histochemical stain for Ca2+ deposits, showed an increased number of positive fibers in the DMD muscle compared to controls.

Necrotic and non-necrotic fibers were alizarin positive (34). It was found that the total Ca2+ content of DMD muscle biopsies was increased by a factor of 2.4 compared to controls (228). A similar increase in Ca2+ was observed in adult mdx muscles at all stages tested (157). The mechanism of Ca2+ entry and its link to dystrophin deficiency are still controversial. Increased activity of Ca2+ channels of the plasma membrane in the original DMD and mdx myotubes has been reported (138, 207). High levels of intracellular free Ca2+ detected with fluorescent indicators were observed in DMD myotubes (355) and mdx muscle fibers (525). These data suggest a direct or indirect involvement of dystrophin in ca2+ muscle homeostasis and a close correlation between dystrophin deficiency and increased Ca2+ inflow. In subsequent studies, these results could not be confirmed. Several groups showed unchanged free Ca2+ rest values and Ca2+ transients in cultured myotubes of DMD and mdx origin (407, 428) and in mdx muscle fibers (146, 185, 407). Interestingly, hyposmotic stress, a way to mimic mechanical stress, induced Ca2+ transients in myotubes (407), and they were more pronounced in mdx myotubes (298).

Contracted but non-dormant DMD myotubes co-cultured with spinal cord tissue were more sensitive to hyposmotic shock than controls (223). ACh is broken down into acetyl and choline by the enzyme acetylcholinesterase (AChE). AChE is located in the synaptic cleft and breaks down ACh so that it does not remain bound to ACh receptors, which would lead to prolonged unwanted muscle contraction. When a neurotransmitter binds, these ion channels open and Na+ ions cross the membrane into the muscle cell. This reduces the voltage difference between the inside and outside of the cell, which is called depolarization. Since the ACh binds to the engine end plate, this depolarization is called end plate potential. Depolarization then spreads along the sarcolemma and along the T tubules, creating an action potential. .