BIOENERGETICS OF SKELETAL-MUSCLE IN MITOCHONDRIAL MYOPATHY

(31)Phosphorus nuclear magnetic resonance spectroscopy was used to examine skeletal muscle in 29 patients with mitochondrial myopathy, 9 male and 20 female. Gastrocnemius was investigated in 15 patients and 30 normal subjects and finger flexor muscle (flexor digitorum superficialis, fds) in 24 patients and 35 normal controls. Both muscles were studied in 10 of the patients. Results were abnormal (outside the full range of normal values) in all but 2 patients. In 86% of patients (25/29) abnormalities were detected in resting muscle. In most cases there was a low phosphocreatine/ATP ratio, high calculated free [ADP] and low phosphorylation potential. At rest, abnormality was detected with equal ease in fds and gastrocnemius. Exercise and recovery increased the sensitivity of MRS in detecting abnormal metabolism. Finger flexion was better tolerated by patients than plantar flexion and gave bigger changes in metabolite concentrations and intracellular pH. Thus, results from fds were more easily differentiated from normal. Exercise duration was significantly shorter than in controls while phosphocreatine depletion was more rapid than normal, consistent with a shortfall in mitochondrial ATP synthesis. Nearly all patients (25/27, 93%) showed abnormalities during recovery from exercise. [ADP] was high during exercise and its recovery was delayed, providing increased drive for oxidative phosphorylation. Phosphocreatine resynthesis during recovery (which reflects oxidative ATP synthesis) was slow both in absolute terms and in relation to [ADP]. Recovery of intracellular pH after exercise was significantly more rapid than normal, consistent with an upregulation of proton efflux. Analysis of phosphocreatine and ADP recovery data suggest that mitochondrial control is near-normal in some patients, but confirm that in the more severely affected subjects the maximum capacity of the mitochondria is reduced. Significant correlations of MRS abnormalities with the degree of muscle weakness were found at rest, during exercise and, especially, in recovery. There was no obvious relationship between the MRS findings and clinical features such as eye signs, seizures, intellectual impairment or muscle pain, or with the genetic lesion.