Abstract:
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Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disorder, affecting 1 in 3500 male births. Skeletal muscle lacking dystrophin exhibit mitochondrial function abnormalities, including a reduced capacity for oxidative phosphorylation (Even, 1994; Kuznetsov, 1998) and a decrease in the expression of numerous mitochondrial genes (Chen, 2000). This situation has been termed a "metabolic crisis". In this study, we focus upon the concept that impaired mitochondrial function in DMD skeletal muscle plays a key role in sustaining several of the pathophysiological events found in DMD and that mitochondrial function can be beneficially modulated in dystrophindeficient skeletal muscles. To test this hypothesis, we examined the effects of activating AMP-activated protein kinase by 5-aminoimidazole-4-carboxamide (AICAR), a known inducer of mitochondrial biogenesis (Narkar, 2008). We firstly evaluated the effects of short-term (2 days) AICAR treatment (0.5g/g/day ip) on the different known targets of AMPK. In this regard, the ratios of phosphoAMPK/AMPK and phosphoACC/ACC were increased both in vivo (n=6-7, p<0.05) and in primary muscle cell cultures from mdx mice. We next tested the effect of long-term (4 weeks) AICAR therapy at the same dose on skeletal muscle function and pathology in mdx mice. Regarding mitochondrial biogenesis, mitochondrial complexes I and V were significantly higher in the quadriceps (p<0.05) of treated mice. Because of its more severe phenotype in mdx mice, we also examined effects on diaphragmatic contractile function. In treated mdx mice, there was a significant increase (21%) in maximal diaphragmatic force production (p<0.01). Histological analysis revealed that in AICAR-treated mdx mice, the diaphragm had a decreased percentage of central nuclei (p<0.001), while total muscular area (54.1±2.7 vs 55.2±1.3%) and of mean individual fiber cross-sectional areas (811.4±61.5 vs 853.7±60.3 ?m2) were not significantly affected. An increase in slow fiber type (MHC I) proportion (+40%) and a decrease in MHC2x/embryonic fibers (-15%) was also observed in diaphragm (p<0.01) after 4 weeks of AICAR therapy. We speculate that the benefits derived from AICAR therapy may be explained by the switch of fibers towards a more oxidative phenotype. These results support a key role for mitochondria in the mdx physiopathological process. Thus, increasing mitochondrial biogenesis could represent a novel therapeutic strategy in the treatment of DMD patients.
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