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The protective role of S-nitrosoglutathione reductase (GSNOR) against excessive NO-dependent S-nitrosylation of myofibrillar and/or Ca2+-handling proteins in mouse fast-twitch skeletal muscle during fatigue and recovery


Skeletal muscle fibers produce nitric oxide (NO) and possibly the S-nitrosylated form of glutathione, S-nitrosoglutathione (GSNO), due to Ca2+ transients during fatigue. GSNO reductase (GSNOR), an enzyme that denitrosylates S-nitrosothiols, scavenges GSNO to protect proteins from being S-nitrosylated. Prior studies have revealed GSNOR as a protective enzyme against excessive S-nitrosylation by GSNO in many tissues, but it has not been shown to directly regulate proteins during fatigue in skeletal muscle. We investigated the role of GSNOR during fatiguing contractions, particularly the acute effects of a pharmacological GSNOR inhibitor (GSNORi), on fast-twitch muscle contractility and fatigue resistance using whole extensor digitorum longus (EDL) muscles and intact single flexor digitorum brevis (FDB) myofibers from mice. GSNORi did not result in any changes in contractile function under non-fatiguing conditions. EDL exposed to GSNORi were less fatigue tolerant and less capable of recovering after fatigue. NO synthase (NOS) inhibitor NG-Methyl-L-arginine (L-NMMA) blocked GSNORi’s effects on fatigue tolerance and recovery. GSNORi treated myofibers exhibited depressed recovery of contractile force post- fatigue compared to controls treated with dimethyl sulfoxide (DMSO), the vehicle used to solubilize GSNORi, matching the EDL data. Myofibers showed no changes in Ca2+-handling or the force-Ca2+ relationship, nor in time to fatigue, thereby contradicting the results of our EDL experiments. These data suggest that NO produced during muscle fatigue leads to an increase in GSNO, which may subsequently lead to an increase in intracellular S-nitrosothiols that specifically alters myofibrillar rather than Ca2+- handling protein function, and that GSNOR regulates against excessive S-nitrosylation of these proteins.

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