Skeletal muscle of patients with Duchenne's muscular dystrophy: evidence of a mitochondrial proteolytic factor responsible for calmitine deficiency.
We studied the effect of mitochondrial extracts of skeletal muscle obtained from patients with Duchenne's muscular dystrophy (DMD) on calmitine of the mitochondrial matrix isolated from skeletal muscle of control mice. Our results in vitro clearly show that calmitine of the mitochondrial matrix of control muscle was degraded in the presence of mitochondrial extracts of muscle from DMD patients. The diseased muscle apparently contains an abnormal calmitine-specific proteolytic factor responsible for the calmitine deficiency previously observed in this tissue. As calmitine binds calcium and probably plays a role in regulating the balance of bound and free calcium within mitochondria, a calmitine deficiency could result in an overload of mitochondrial free calcium. Certain enzymes involved in ATP synthesis would be inhibited, resulting in the muscular degeneration characteristic of this myopathy. Our results suggest the cause of mitochondrial calcium overload and the events leading to muscular degeneration in this disease model. Abnormal protease activity could be the factor triggering all of these processes in the DMD patient. These findings suggest that it may now feasible to search for an efficient pharmacologic treatment for DMD.
Lucas-Heron
B
B
Groupe de Recherche sur les Myopathies, Laboratoire de Physiologie, U.E.R. de Médecine, Nantes, France.
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002135:Calcium-Binding Proteins / Q000378:metabolism; D002155:Calsequestrin / Q000172:deficiency* / Q000302:isolation & purification / Q000378:metabolism; D004272:DNA, Mitochondrial / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D006801:Humans; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins; D018482:Muscle, Skeletal / Q000378:metabolism*; D009136:Muscular Dystrophies / Q000378:metabolism*; D012016:Reference Values; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
C503129:CASQ1 protein, human; D002135:Calcium-Binding Proteins; D002155:Calsequestrin; C503130:Casq1 protein, mouse; D004272:DNA, Mitochondrial; D024101:Mitochondrial Proteins; D010450:Endopeptidases; D002118:Calcium