Altered mitochondrial functions in skeletal muscle of HFHSD mice.

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To investigate whether alterations in mitochondrial density and ultrastructure was associated with mitochondrial dysfunction in skeletal muscle of HFHSD mice, we measured substrate-driven oxygen consumption in saponin-skinned skeletal muscle fibers. When mice were fed with a HFHSD for 4 weeks, the respiration rates were not different from SD mice, whatever were the tested substrates (Table 2). In muscle fibers from 16 week HFHSD mice, respiration with complex 1-linked substrates (Glutamate/Malate), but not with complex 2-linked substrates (Succinate/Rotenone), was significantly reduced, both during state 3 and state 4, when compared to SD mice (Table 2). In addition, we observed a significant decrease of oxidation capacities when using octanoyl or palmitoyl-carnitine as substrates in fibers of 16 week HFHSD mice. Taken together, these data demonstrate that complex 1-linked respiration and b-oxidation were decreased specifically in diet-induced diabetic mice. Reduced oxidation of fatty acids was probably not related to altered availability of the substrates since genes involved in muscle fatty acid uptake (FAT/CD36) and entry in the mitochondria (CPT1) were significantly up-regulated in skeletal muscle of 16 week HFHSD mice (Figure S3A). Further supporting a reduction of the mitochondrial functions, a decreased activity of succinate dehydrogenase was evidenced by succinate dehydrogenase staining in gastrocnemius histological sections in 16 week-, but not in 4 week HFHSD mice (Figure S3B).