D.P.16 Metabolic and hemodynamic alterations in the mdx skeletal muscle revisited using multi-parametric functional NMR

Abstract

The mdx mouse remains a popular model of the Duchenne muscular dystrophy. While criticized for the mild impairment of muscle function and structure, the mdx remains highly relevant in terms of energy and microvascular control disturbances associated to muscle dystrophy. In this study, a non-invasive multi-parametric functional NMR approach (mpf) was used to revisit these anomalies. This NMR approach interleaved arterial spin labeled imaging and 31P spectroscopy to measure perfusion, capillary oxygenation and muscle energetics of the gastrocnemius of C57Bl/10wt and mdx mice (between 10 and 65weeks of age). Hind-limb ischemia (30min) or repeated bouts of exercises (2min) and recovery were investigated. After ischemia, phosphocreatine (PCr) depleted more in 28-week-old mdx vs wt mice (ΔPCr: 82±6% vs 62±10%). Resynthesis of PCr at reactive hyperemia appeared prolonged (TCr: 88.7 ±21.5s vs 53±23.3s). In parallel, vasodilatation lasted less at reactive hyperemia in mdx mice compared to wt mice. Similarly, a shorter reperfusion profile was visible in 65-week old mdx mice following exercise, confirming a default in maintaining vasodilatation in old mdx vs old wt mice but also compared to young mdx mice. Moreover capillary oxygenation at reactive hyperemia showed reduced O2 extraction in mdx mice. In this study, the mpf-NMR protocol proved again its capacity to characterize in vivo functional anomalies, this time in dystrophic muscle. The underlying mechanisms require further investigation, with neuronal NO synthase (nNOS) deficiency most likely playing a direct role in the perfusion profile alterations. The defective nNOS might also contribute indirectly, through PFK inhibition, to the faster PCr depletion during ischemia, which could be indicative of impaired glycolysis. On the other hand, the slower PCr resynthesis and lower oxygen extraction help to appreciate and quantify the real impact in vivo of mitochondrial dysfunction in mdx.