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Role of nNOS signaling in skeletal muscle
Neuronal nitric oxide synthase (nNOS) use oxygen to catalyze the production of nitric oxide (NO) from arginine (see diagram). NO is a reactive gas that can act through cGMP dependent (activativation of soluble guanylyl cyclase) or cGMP independent pathways (S-nitrosylation). Despite its name, nNOS is expressed at high levels in skeletal muscle. There are two nNOS signaling compartments in skeletal muscle based on nNOSμ and nNOSβ. Cardiac muscle expresses only nNOSμ. nNOSμ is found at the sarcolemma, bound to α -syntrophin, a member of the dystrophin glycoprotein complex. Loss of dystrophin (and syntrophin) that occurs in Duchenne muscular dystrophy causes nNOSμ to be lost from the sarcolemma. One consequence of nNOSμ mislocalization is that muscle cannot properly regulate blood supply during exercise (ref- Thomas). We were the first to show that nNOSμ is a important regulator of skeletal muscle fatigue. nNOSβ is found at the Golgi and is a critical regulator of skeletal muscle mass, strength and fatigue. We are focused on understanding the mechanisms that regulate nNOS isoform localization in muscle and on the roles of nNOS isoforms in regulating muscle performance, particularly in muscle wasting diseases such as Duchenne muscular dystrophy.

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