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The neuromuscular system includes all the muscles of the body and the nerves that serve them. In some disease conditions, smooth muscle cells take on a non-contractile phenotype. Although these cells still have signaling machinery that increases intracellular calcium levels, they have significantly reduced calcium intake through blood pressure-driven calcium channels. Therefore, there is a shift to intracellular release of calcium fueled by storage, similar to the changes seen in cardiac hypertrophy. Concurrent with a decrease in serca, RyR2, PMCA1 and sodium/calcium exchanger levels, levels of STEM, ORAI (proteins associated with the replenishment of intracellular calcium stores; see Bootman 2012), SERCA2B and IP3R increase and there is a change in RyR receptor subtypes from RyR2 to RyR3 (Lipskaia and Lompre 2004; Berra-Romani et al., 2008; Baryshnikov et al. 2009; Matchkov et al., 2012). Together, these changes reflect a less contractile phenotype. Because the ATP produced by creatine phosphate is depleted, muscles turn to glycolysis as a source of ATP. Glycolysis is an anaerobic (non-oxygen-dependent) process that breaks down glucose (sugar) to produce ATP; However, glycolysis cannot produce ATP as quickly as creatine phosphate. Thus, the switch to glycolysis leads to a slower availability of ATP from the muscle. The sugar used in glycolysis can be provided by blood sugar or by metabolizing glycogen stored in the muscle.

The breakdown of one glucose molecule produces two ATP and two pyruvic acid molecules, which can be used in aerobic respiration or at low oxygen levels, which can be converted into lactic acid (Figure 6). Calcium triggers a contraction in the striated muscle. (A) Actomyosin in striated muscles. (1) The striped muscle in the relaxed state has tropomyosin, which covers the sites of binding to myosin on actin. (2) Calcium binds to troponin C, which induces a conformational change in the troponin complex. This causes tropomyosin to penetrate deeper into the actinrillilla and expose the myosin binding sites. (B) Transverse bridge cycle in striated muscles. (1) Calcium binds to troponin C and causes conformational displacement to tropomyosin, which reveals myosin binding sites to actin. (2) ATP then binds to myosin.

(3) The ATP is then hydrolyzed. (4) A transverse bridge forms and myosin binds to a new position on actin. (5) Pi is released and the myosin changes the conformation, resulting in the force impact that causes the filaments to slide over each other. (6) ADP is then released. (C) Contraction in smooth muscles. In smooth muscle, calcium binds to calmodulin and causes activation of myosin light chain kinase (MLC) (MLCK). This phosphorylate MLC, which then binds to actin to form phosphorylated actomyosine, allowing the transverse bridge cycle to begin. Muscle contraction usually stops when motor neuron signaling ends, which repolarizes the sarcolemma and T tubules and closes the voltage-controlled calcium channels in the SR. The Ca++ ions are then pumped into the SR, allowing tropomyosin to protect (or cover) the binding sites on the actin strands. A muscle can also stop contracting when it lacks ATP and fatigue (Figure 2). Signal transduction is essential for the function of contractile cells.

The stimulating signal leads to an increase in cytosolic calcium levels, which activates muscle contraction. We now know the main causes of different types of muscle contraction and have a better understanding of the changes that occur in the contractile apparatus under training and pathophysiological conditions. For example, the identification of PGC1α as the primary regulator of upwardly regulated transcription factors in trained and pathological striped muscles offers new ways to modulate muscles in a therapeutic environment. It is also evident that many signaling proteins in smooth and striped muscles are activated by changes in cytosolic calcium levels, and these signaling pathways often lead to changes in gene expression. Now that we have a better understanding of the changes that occur in the contractile apparatus under pathophysiological conditions, this knowledge can be used to strategically treat diseases. Heart failure also leads to upward regulation of molecules that may have a protective function. One way is via cGMP, which promotes relaxation. The cGMP signaling pathway is regulated by cGMP-directed phosphodiesterases, one of which, PDE5A, appears to be a promising target for protective treatment against hypertrophy. Once intracellular calcium levels are elevated, calcium binds to either troponin C on actin filaments (in striated muscles) or calmodulin (CaM), which regulates myosin filaments (in smooth muscles). In striated muscle, calcium causes a change in the position of the troponin complex into actin filaments, exposing the myosin binding sites (Fig. 2A).

Myosin, bound by ADP and inorganic phosphate (Pi), can then form transverse bridges with actin, and the release of ADP and Pi creates the power stroke that causes contraction. This force causes the thin actin filament to slide past the thick myosin filament and shortens the muscle. Binding ATP to myosin then releases myosin from actin, and myosin hydrolyzes ATP to repeat the process (Fig. 2B). Muscles move on the controls of the brain. The individual nerve cells in the spinal cord, called motor neurons, are the only way the brain connects to the muscles. When a motor neuron fires in the spinal cord, an impulse passes from it to the muscles on a long, very thin extension of that single cell called an axon. When the pulse descends along the axon to the muscle, a chemical is released at its end. Muscles are made up of long fibers that are long connected to each other by a ratchet mechanism, the type of mechanism that allows both parts of an extension conductor to slide on top of each other and lock into a certain position. When the motor neuron`s chemical impulse hits the muscle, the muscle fibers pass and overlap more, making the muscle shorter and bigger. When the impulses of the nerves stop, the muscle fibers slide to their original positions.

In the stomach muscle, rhythmic contractions are due to the activity of pacemaker cells, but activation of tension-controlled calcium channels can trigger the entry and contraction of calcium. Sympathetic nerves run along smooth vascular muscles and can release stimuli such as acetylcholine, norepinephrine, angiotensin, and endothelin. In addition, circulating blood factors such as cytokines and diffusible factors such as nitric oxide can also act on plasma membrane receptors or cross the plasma membrane to regulate pathways that control intracellular calcium levels. Activation of receptor-fed channels (ROC) also causes an influx of calcium, allowing for additional release of calcium from intracellular reserves. GPCRs allow PLCβ to generate IP3s, which release calcium via IP3Rs. In smooth vascular muscles and circular smooth muscles of the intestine, the main isoform is IP3R1. Note, however, that there is some heterogeneity. In the smooth longitudinal muscles of the intestine, RyRs are expressed instead of IP3Rs.

Agonists such as cholecystokinin bind to the GPCR CHOLECYSTOKININ A receptor (CCK-AR), which activates phospholipase A2, which in turn produces arachidonic acid. Arachidonic acid (AA) can also be produced by dividing DAG. AA activates chloride channels that depolarize the cell membrane and allow the opening of voltage-dependent calcium channels and an initial influx of calcium. This calcium can either act directly on the RyR that causes the ICRC, or allow the release of cyclic ADP ribose that interacts with the RyRs to improve the ICRC. DMD is an inherited disease caused by an abnormal X chromosome. It mainly affects men and is usually diagnosed in early childhood. DMD usually occurs first as a difficulty with balance and movement, and then develops into an inability to walk. It progresses higher in the body from the lower limbs to the upper body, where it affects the muscles responsible for breathing and circulation. It eventually causes death due to respiratory failure, and sufferers usually do not live beyond the age of 20.

In the heart muscle, depolarization begins in the pacemaker cells (modified cardiac myocytes that adjust the heart rate and are rich in signaling molecules) in the sinus node, which is innervated by the parasympathetic and sympathetic nerves. External stimuli modulate the activity of pacemaker cells – they undergo spontaneous self-depolarization to generate action potentials. This is achieved by a slow leakage of potassium ions and a simultaneous influx of sodium and calcium ions. The action potential then reaches the cardiac myocytes, where it enters the tubule T. However, unlike skeletal muscle, where L-type calcium channels are directly coupled to RyRs, the influx of calcium through the plasma membrane into cardiomyocytes triggers the release of calcium by SR via RyRs by ICRC (Fig. 4B). The predominant isoform in the heart is RyR2. As in skeletal muscle, contraction is controlled by phosphorylation of troponin, but can also be modulated by calcium CaM and MLCK. Mice with non-phosphorylable MLC in ventricular myocytes exhibit depressive contractile function and develop atrial hypertrophy and dilation (Sanbe et al., 1999).

Muscle fatigue occurs when a muscle can no longer contract in response to signals from the nervous system. The exact causes of muscle fatigue are not fully known, although some factors have been correlated with the decrease in muscle contraction that occurs during fatigue. ATP is necessary for normal muscle contraction, and when ATP stores are reduced, muscle function may decrease. This may be more of a factor in short, intense muscle performance than in sustained, less intense exertion. .