Muscular Dystrophy

An additional area of research in the lab is to identify and characterize molecular mechanisms that underlie muscle damage and repair in a Drosophila myopathy model. Recent molecular characterizations of myopathies and muscular dystrophies have revealed a striking complexity of muscle diseases in humans.  Muscular dystrophies can arise from mutations affecting structural proteins, sarcoglycan membrane proteins, nuclear membrane proteins, and enzymes, leading to progressive weakness and degeneration of skeletal muscles. These disorders may also functionally denervate the muscle by disruption of postsynaptic receptor clustering at the synapse.  Though much has been learned from the molecular characterization of myopathies, it remains unclear how diseased fibers alter neuromuscular function.  In addition, whether disease-triggered reorganization of the actin cytoskeletal network within muscle contributes to or partially alleviates muscle dysfunction is unknown.  The genetic tractability of Drosophila has made it an ideal system to characterize mutations affecting neuromuscular function. To further analyze the pathology associated with muscular dystrophy, we have generated a hypercontraction-induced myopathy model using dominant mutants in the Myosin heavy chain (Mhc) locus in Drosophila.  These mutants are caused by single amino acid changes within the ATP binding/hydrolysis domain of Mhc and lead to degeneration of the flight muscles.  Electrophysiological analysis has revealed temperature-dependent seizure activity in dystrophic adult muscles.  In addition, larval physiology demonstrates spontaneous muscle movements in the absence of neuronal stimulation and extracellular Ca²⁺, indicating a dysregulation of intracellular Ca²⁺ homeostasis in damaged muscles.  Utilizing genome-wide DNA microarray analysis, we have determined the transcriptional response to muscle dysfunction in Drosophila, revealing a conserved muscle remodeling pathway similar to mammalian myopathy models.  The altered gene expression includes upregulation of several classes of actin binding proteins, suggesting cytoskeletal remodeling pathways in damaged muscle may potentially counteract the effects of primary muscle dysfunction.  We are now characterizing the functional consequences of the transcriptional response to myopathy and using the genetic tractability of Drosophila to identify mechanisms underlying degeneration and repair of dystrophic muscles.