The specific objective of these studies is to discriminate between the potential influences of mechanical perturbations at the sarcolemmal membrane from those of disrupted cross bridge function in the onset of Duchenne's muscular dystrophy (DMD). We will also address the possibility that cytosolic calcium handling is compromised during the early stages of the disease process. DMD is the most common and severe of the muscular dystrophies affecting in widespread fashion, skeletal, smooth and heart muscle. The loss of dystrophin, and additional proteins of the dystrophin-glycoprotein complex from the muscle membrane characterize DMD. This deficiency is thought to render the membrane susceptible to injury, leaky to Ca 2+, disrupted for cell signaling, or a combination of these. Unfortunately, the specific biological mechanisms that initiate DMD are not yet known. It is therefore critical to determine the specific mechanisms responsible for DMD very early in maturation to develop therapeutic approaches to blunt or even eliminate its onset. We will assess skeletal muscles from pups of control, mdx, utrophin -/- (utrn -/-) and mdx:utrn -/- mice (a mouse model of DMD that lacks both dystrophin and its homolog, utrophin) at several ages between 7-28 d. We will test the overarching hypothesis that attenuated dystrophic skeletal muscle function during early maturation is due to disruptions in the contractile apparatus and/or calcium handling rather than due to mechanical instability of the sarcolemma.
In Specific Aim 1, we will test the hypothesis that overall muscle force generating capability is decreased independent of membrane damage.
In Specific Aim 2 we will determine if the force loss is due to a compromised contractile apparatus.
In Specific Aim 3, we will test the hypothesis that the force loss is due to disrupted cytosolic calcium handling. These studies will delineate the contribution of mechanical influences at the membrane from those of disrupted cross bridge function in the onset of DMD, as well as determine the role of calcium handling. These studies will provide valuable insight for the development of therapeutic interventions to prevent the onset of DMD.
