352 Quantitative and qualitative mitochondrial adaptations of substrates utilization in cardiac and skeletal muscles

have recently shown that knocking out of endothelium NOS (eNOS) induces an important reduction of mitochondrial oxidative capacity specifically in slow-twitch muscle (soleus, Sol) (Momken et al. 2002, Biochem J, 368:341-7). To examine the functional consequences of eNOS inhibition, physical capacity of mice, null for eNOS isoform, was estimated using a voluntary wheel-running program. In parallel, we studied energy metabolism enzyme profiles and their response to voluntary exercise in cardiac, Sol and fast-twitch gastrocnemius (Gast) skeletal muscles. Running distance, work, running speed and distance per run (mean distance the mice run each time they use the wheel) over the 8 week program were calculated after continuous recording of the output voltage of the DC generator on a PC computer. Weekly averaged work and running distance were two times lower for eNOS-/mice (608±65 J/day and 4.09±0.42 km/day) than for control (1207±74 J/day, p<0.01 and 7.74±0.42 km/day, p<0.01). The average maximal running speed was 19% (p<0.01) and the distance per run was 50% (p<0.01) lower in eNOS-/-mice. Furthermore, our study showed that physical activity influenced the adaptation to exercise specifically in Sol muscle. Physical activity increased significantly Sol weight by 22% (p<0.05) in wild-type mice but not in eNOS-/mice. Control Sol did not change its metabolic profile, in contrast to eNOS-/muscle where exercise decreased cytochrome c oxidase (COX) (-36%, p<0.05), citrate synthase (-37%, p<0.06) and creatine kinase (-24%, p<0.01) activities. Exercise changed energy enzyme profile neither in heart nor in Gast muscle (the only exception was a 44%, p<0.05 decrease in COX activity in active Gast muscle). Thus, in the absence of eNOS-derived NO, exercise induces a down-regulation of energy metabolism specifically in slow-twitch muscle. These results suggest that eNOS might be important for maintaining a suitable physical capacity and that its down-regulation might participate in intolerance to exercise.