Deletion of SIRT1 in the skeletal muscle decreases type IIa oxidative muscle fiber in mice.

Abstract

Background and AimSIRT1 is an NAD+‐dependent protein deacetylase, which exerts cytoprotective effects. We previously reported that resveratrol, an activator of SIRT1, improves exercise tolerance with upregulation oxidative type of muscle fibers in a mouse model of Duchenne muscular dystrophy. SIRT1 deacetylates and activates PGC‐1α, a co‐activator to promote expression of oxidative muscle fibers. The purpose of this study was to examine whether SIRT1 maintains oxidative muscle fibers for exercise capacity in the skeletal muscle using muscle‐specific SIRT1 knockout mice (SIRT1MKO).Methods and ResultsWe first compared the expression level of SIRT1 in several types of skeletal muscles in wild‐type mouse (WT). The SIRT1 protein level was the highest in the soleus muscle (+3.5‐fold), which is mainly made up of oxidative fibers, compared to the other glycolytic muscles such as quadriceps, gastrocnemius, tibial anterior, and extensor digitorum longus muscles. The SIRT1 mRNA level was most abundant also in the soleus. Immunohistological analysis using soleus muscle sections showed that the percentage of type IIa, one of oxidative muscle fibers, was significantly lower in the SIRT1MKO than that in WT (42% vs. 56%) at 26–32 months old. In contrast, the percentage of glycolytic type IIx+IIb muscle fibers was higher in the SIRT1MKO (15%) compared to WT (11%). Treadmill running distance at 30 months old was significantly shorter in SIRT1MKO (78±8 m) than that in WT (592±10 m).ConclusionThese results suggest that deletion of SIRT1 in the skeletal muscle reduces exercise capacity by decreases type IIa oxidative muscle fiber.