The CRG 192
Our clinical research group (CRG) program project grant application is dedicated to elucidating regulation and dysreglation of skeletal muscle.
Alteration in the size and functional capacity of skeletal muscle is a hallmark symptom of muscular dystrophy. However, the process also occurs in common acquired skeletal muscle disorders, such as the cachexia of chronic illnesses.
The regulatory mechanisms are largely unknown. Disuse could be involved, although hibernating animals conserve their muscle strength despite disuse.
A massive increase in muscular development is also a feature in myostatin-related (a TGF-beta-superfamily protein) genetic disorders in animals and man, although the hypertrophy is not associated with a concomitant increase in functional capacity.
We have preliminary evidence that an interaction between myostatin and dysferlin, a protein responsible for limb-girdle muscular dystrophy, may exist. Since myostatin inhibits muscle cell growth, we also hypothesize that the devastating childhood cancer, rhabodmyoscarcoma, might involve myostatin dysfunction.
Transport across the nuclear membrane appears crucial to muscle diseases, since mutations in lamin A/C causes various muscle disease. Lamin A/C mutations cause much more than skeletal or cardiac muscle disease. Dunnigan’s familial partial lipodystrophy is associated with substantial, but functionally useless, muscle hypertorphy, as well as the metabolic syndrome, fatty liver, and reduced exercise tolerance. SMAD transport, a TGF-beta-related pathway, may be influenced by these mutations.
Little is known about how stem cells are differentiated to skeletal muscle cells. The role of Wnt signaling, so vital to so many processes, has not been addressed in this regard. Recently, ahnak has been identified as an L-type calcium channel regulatory protein in muscle. Ahnak is anchored to the sarcolemma by dysferlin, the protein implicated in limb girdle muscular dystrophy 2B. Ahnak has not been studied in human disease.
We present a unique interdisciplinary program that includes molecular and cell biologists, neurologists, internists, critical care specialists, and clinical pharmacologists. We believe that our CRG brings together scientists and clinician/scientists who seldom communicate with one-another.
