CELLULAR ENERGETICS OF DYSTROPHIC MUSCLE

Cytosolic pH and phosphorus metabolite ratios in skeletal muscle were measured by P-31 magnetic resonance spectroscopy in patients with Duchenne muscular dystrophy (DMD) and Becker's muscular dystrophy (BMD) and in Duchenne/ Becker carriers. In resting dystrophin-deficient muscle, there was a decrease in phosphocreatine (PCr) and increase in orthophosphate (P(i)) relative to ATP, and an increase in calculated free [ADP]. Phosphomonester and phosphodiester were also increased relative to ATP. These changes were largest in DMD, smaller in BMD and small or absent in carriers. Cytosolic pH was increased substantially in DMD, moderately in BMD and slightly but significantly in gastrocnemius of carriers. Raised intracellular pH thus appears to be the most characteristic abnormality in dystrophin-deficient muscle. Responses to aerobic exercise were studied in the forearm muscle flexor digitorum superficialis of carriers. PCr depletion during exercise was greater than normal but the fall in pH was disproportionately small, resulting in increased [ADP]. This is likely to result either from reduced anaerobic glycogenolysis to lactic acid or from increased proton efflux (as is seen in mitochondrial myopathy). Detailed analysis suggests: (1) at the start of exercise, calculated lactic acid production was increased, as was the rate of PCr depletion, suggesting that there was no absolute defect of glycogenolysis. (2) At the start of recovery, calculated proton efflux was not increased, although as the pH at the end of exercise was higher than in controls and proton efflux is normally pH-dependent, an up-regulation of proton efflux cannot be excluded. (3) Recovery of PCr, P(i) and ADP after exercise were not impaired, suggesting that mitochondrial function is normal.