SKELETAL-MUSCLE OF PATIENTS WITH DUCHENNES MUSCULAR-DYSTROPHY - EVIDENCE OF A MITOCHONDRIAL PROTEOLYTIC FACTOR RESPONSIBLE FOR CALMITINE DEFICIENCY

We studied the effect of mitochondrial extracts of skeletal muscle obt ained from patients with Duchenne's muscular dystrophy (DMD) on calmit ine of the mitochondrial matrix isolated from skeletal muscle of contr ol mice. Our results in vitro clearly show that calmitine of the mitoc hondrial matrix of control muscle was degraded in the presence of mito chondrial extracts of muscle from DMD patients. The diseased muscle ap parently contains an abnormal calmitine-specific proteolytic factor re sponsible for the calmitine deficiency previously observed in this tis sue. As calmitine binds calcium and probably plays a role in regulatin g the balance of bound and free calcium within mitochondria, a calmiti ne deficiency could result in an overload of mitochondrial free calciu m. Certain enzymes involved in ATP synthesis would be inhibited, resul ting in the muscular degeneration characteristic of this myopathy. Our results suggest the cause of mitochondrial calcium overload and the e vents leading to muscular degeneration in this disease model. Abnormal protease activity could be the factor triggering all of these process es in the DMD patient. These findings suggest that it map now feasible to search for an efficient pharmacologic treatment for DMD. (C) 1996 Academic Press, Inc.