nNOS Signaling in Skeletal Muscle
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nNOS Signaling in Skeletal Muscle
NO (Nitric Oxide) is formed endogenously by a family of enzymes known as NOS (NO Synthases). The distribution of different isoforms of NOS is largely related to their respective functions. Three distinct isoforms of NOS have been identified: nNOS (also known as NOSI and NOS-1) being the isoform first found (and predominating) in neuronal tissue, iNOS (also known as NOSII and NOS-2) which is inducible in a wide range of cells and tissues and eNOS (also known as NOSIII and NOS-3) isoform first found in vascular endothelial cells. NO plays several important roles in the brain, including in regulation of synaptic signaling and plasticity. Additionally, high levels of nNOS protein are present in skeletal muscle, where NO controls muscle contractility and local blood flow (Ref.1).

NO is generated via a five-electron oxidation of a terminal guanidine nitrogen on L-Arginine. The reaction is both oxygen and NADPH-dependent and yields L-Citrulline in addition to NO, in a 1:1 stoichiometry. NO functions as an endogenous signaling molecule in numerous organs and tissues throughout the animal and plant kingdoms. The most important regulator of nNOS activity is free cytosolic Ca2+, which stimulates nNOS through interaction with Calm (Calmodulin). Arrival of action potentials activates CaCn (Voltage-dependent Ca2+ Channels) situated in the neurolemma, and stimulates the release of Ca2+ from intracellular stores. This elevates cytosolic Ca2+ concentrations required for Calm binding to nNOS, thereby activating the enzyme. When the concentration of Ca2+ falls, it dissociates from the Calm, which in turn dissociates from the nNOS, thus acting as a switch that turns the enzyme on and off. Skeletal muscle nNOS-Mu is bound to the Dystrophin-associated protein complex through interaction of the nNOS-Mu PDZ domain. nNOS does not bind to Dystrophin directly, but rather is targeted to the sarcolemma via Syntrophins (Snt-Alpha1, Snt-Beta1, Snt-Beta2), a Dystrophin-associated protein that is predominantly expressed in skeletal and cardiac muscle. This nNOS-Syntrophin PDZ-PDZ complex is essential for sarcolemmal association of nNOS. The loss of Dystrophin in Muscular Dystrophy prevents assembly of the Dystroglycan Complex. As a result, NO signaling in response to muscle contraction is disrupted, and, the blood vessel dilation of contracting skeletal muscle that is normally mediated by NO is abolished (Ref.2). Similar to nNOS-Alpha in brain, nNOS-Mu protein turnover in skeletal muscle is also regulated by Ca2+-dependent Calpain degradation. In skeletal muscle, nNOS activity is related to muscle AChR (Acetylcholine Receptors) and membrane depolarization (Ref.3 & 5).

The actions of NO are a consequence of its influence on a variety of protein functions which it exerts through its reaction with Cysteine Thiol, S-Nitrosylation, and transition metal centers. Disruption of NO signaling plays a major role in Muscular Dystrophy pathophysiology. Several muscular diseases have been linked to a Dystrophin deficiency. A mutation in the rod-like domain of Dystrophin causes Beckers Dystrophy and results in a loss of sarcolemmal nNOS, while other components of the Dystrophin Complex are preserved. Sarcolemmal instability in Duchenne Dystrophy leads to a repeated cycle of myofiber degeneration and subsequent regeneration. Redistribution of nNOS from sarcolemma to cytosol is involved in myofiber necrosis, whereas the involvement of NO in myofiber differentiation in altered sarcolemmal nNOS signaling contributes to failed muscle regeneration in Duchenne Dystrophy. NO derived from nNOS-Mu in skeletal muscle fibers plays a major role in dilating blood vessels adjacent to contracting skeletal muscle. This physiological response, functional hyperemia, plays an important role in increasing blood flow to contracting skeletal muscles to support their enhanced metabolic needs. Certain mutations of the Dystrophin Complex that cause a mild Muscular Dystrophy uniquely disrupt sarcolemmal nNOS. Loss of skeletal muscle NO does not itself cause dystrophy; the lack of nNOS in Duchenne Muscular Dystrophy augments the damage caused by absence of the structural Dystrophin-Glycoprotein Complex. Because restoring nNOS ameliorates muscle injury in muscular dystrophy, NO donors may offer a potential avenue for therapy (Ref.4).