The Sarcolemma in FSHD and in the myd Mouse

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DESCRIPTION (provided by applicant): Facioscapulohumeral Muscular Dystrophy (FSHD) affects 1 of every 20,000 adults in this country. FSHD has been linked to deletions at the telomeric region of chromosome 4 (4q35-4q35ter), and is inherited as a dominant trait. Although we have learned a great deal about the genetic defects that lead to FSHD, we still know very little about the effects these defects have at the level of individual muscle fibers. Indeed, the cell biological changes that result in muscle weakness and myofiber degeneration have never been studied. Here we propose to address this issue by examining human biopsied materials using ultrastructural techniques and immunofluorescence coupled with confocal laser scanning microscopy. We postulate that, like other human dystrophies, such as Duchennes, Beckers, and some limb girdle muscular dystrophies, the sarcolemma of FHSD muscle is altered in ways that lead to muscle weakness and ultimately to muscle degeneration. In support of this hypothesis, our preliminary studies show that the sarcolemma of FSHD muscle has frequent interruptions in its membrane skeleton, is separated from the nearest myofibrils by a considerable gap, and is organized irregularly, and most closely resembles the sarcolemma of slow twitch muscle fibers although the myoplasm is rich in fast twitch myosin. We propose to pursue three aims in our exploratory studies of FSHD muscle that will: (i) test the validity of these observations and to extend them, if possible; (ii) compare them to other human muscular dystrophies; and (iii) study the biomechanical properties of the sarcolemma, to learn if they are compromised by FSHD. Our final aim will: (iv) examine the sarcolemma of the myd mouse, which has been proposed as a possible animal model of FSHD. Our laboratory has developed an unique set of methods and antibodies that permit us to examine the overall organization of the sarcolemma and its relationship to the nearby contractile apparatus. In the past year, we have adapted these methods for use with snap frozen biopsies of human skeletal muscle. We therefore anticipate making significant progress in understanding the cell biological changes that occur in FSHD skeletal muscle, and in determining which, if any, of these changes are related to the pathophysiology of FSHD.