FIG. 2.

Inhibition of GSNOR-mediated denitrosylation enhances skeletal muscle strength and fatigue resistance. (A–D) The isometric tetanic force-generating capacity of TA muscles in anesthetized 6 month-old wild-type (WT, +/+) and GSNOR^−/− (−/−) mice. (A) Maximum tetanic force output was similar between GSNOR^−/− and WT muscles. (B) Specific force was significantly increased in GSNOR^−/− TA, indicating increased muscle strength. For (A, B), n = 9 for both groups. (C) Tetanic force output, normalized to initial force, was similar between WT and GSNOR^−/− TA muscles at all stimulation frequencies, suggesting normal neuromuscular synapse function. n = 8 for both groups. (D) Specific force was unaffected at stimulation frequencies <50 Hz in GSNOR^−/− muscle; however, GSNOR^−/− muscles were significantly stronger than WT controls at frequencies between 50 and 200 Hz. n = 8 for both groups. (E) Fatigue resistance and post–fatigue force recovery of TA muscles. GSNOR^−/− mice sustained significantly greater force output during the 60–160 s period (gray box), indicating enhanced fatigue resistance. Force recovery after 1, 3, and 5 min was similar between WT and GSNOR^−/− mice. n = 9 and 8 for wild-type and GSNOR^−/− groups, respectively. (F–I) Impact of GSNOR deficiency on the isometric twitch properties of TA muscles in vivo. (F) Maximum isometric twitch force did not differ significantly between WT and GSNOR^−/−. n = 9 and 8 for wild-type and GSNOR^−/− groups, respectively. (G) Specific isometric twitch forces were not significantly different between GSNOR^−/− and WT muscles. (H) The time taken to reach peak (maximum) twitch force in GSNOR^−/− muscle was not different from WT. (I) The time taken to return to half-maximum twitch force was significantly (p < 0.05) longer in GSNOR^−/− muscle compared with WT, consistent with enhanced muscle fatigue resistance. *p < 0.05, **p < 0.01, and ***p < 0.001.