The role of nitrite in muscle function, susceptibility to contraction injury, and fatigability in sickle cell mice

Sickle cell disease (SCD) patients can have limited exercise capacity and muscle dysfunction characterized by decreased force, atrophy, microvascular abnormalities, fiber distribution changes, and skeletal muscle energetics abnormalities. Growing evidence suggests that in SCD there is alteration in nitric oxide (NO) availability/signaling and that nitrate/nitrite can serve as a NO reservoir and enhance muscle performance. Here, we examined effects of nitrite on muscle strength, exercise capacity, and on contractile properties of fast-(extensor digitorum longus, EDL) and slow-twitch (soleus) muscles in SCD mice. Compared to controls, homozygotes (sickling) had decreased grip strength, impaired wheel running performance, and decreased muscle mass of fast-twitch, but not slow-twitch muscle. Nitrite treatment yielded increases in nitrite plasma levels in controls, heterozygotes, and homozygotes but decreases in muscle nitrite levels in heterozygotes and homozygotes. Regardless of genotype, nitrite yielded increases in grip strength, which were coupled with increases in specific force in EDL, but not in soleus muscle. Further, nitrite increased EDL, but not soleus, fatigability in all genotypes. Conversely, in controls, nitrite decreased, whereas in homozygotes, it increased EDL susceptibility to contraction-induced injury. Interestingly, nitrite yielded no changes in distances ran on the running wheel. These differential effects of nitrite in fast- and slow-twitch muscles suggest that its ergogenic effects would be observed in high-intensity/short exercises as found with grip force increases but no changes on wheel running distances. Further, the differential effects of nitrite in homozygotes and control animals suggests that sickling mice, which have altered NO availability/signaling, handle nitrite differently than do control animals.