Grant Duration
07/14 – 06/15

Dysferlin is deficient in a group of muscular dystrophies referred to as dysferlinopathies. Macrophage (Mø)-rich infiltrates and immature muscle fibers are prominent in the milieu of injured skeletal muscles in patients with dysferlinopathy. Recent evidence suggests that Mø are integral in normal muscle repair. Injured skeletal muscle recruits inflammatory Mø (M1) that must transition over time into reparative/regulatory Mø (M2) for the damaged muscle to regenerate. Thus, while M1 driven inflammation is a pre-requisite for repair, the transition to M2 is required for complete healing.

Muscle repair in patients with dysferlinopathy is defective. We propose to test the hypothesis that dysferlinopathy is mediated by a defect in Mø that precludes a sufficient transition from M1 inflammatory to M2 reparative/regulatory phenotypes. This hypothesis is fueled by the following evidence: 1) following transient injury in kidney and skin a defective shift from inflammatory to reparative/regulatory Mø leads to an escalation in inflammatory Mø accumulating in these tissues, ineffective repair and non-resolving inflammation, that in turn triggers immune-mediated disease in susceptible hosts and 2) Mø functions such as adhesion and motility are abnormal in dysferlinopathy patients. To test this hypothesis we will use dysferin deficient BLA/J mice that succumb to a Mø-rich muscular dystrophic process. Currently, there is no effective treatment for patients with dysferlinopathy. Therefore, detailing the role of Mø in the pathogenesis of defective muscle repair in mice with dysferlinopathy offers the promise of uncovering novel therapeutic strategies to treat this illness.

The specific aims are: 1) To test the hypothesis that Mø are defective in shifting from M1 inflammatory to M2 reparative/regulatory phenotypes following muscle injury in dysferlinopathy-prone mice. 2) To test the hypothesis that defective transitioning from inflammatory to reparative/regulatory Mø results from a genetic predisposition and/or the microenvironment.

If our hypothesis is correct, future studies will probe for Mø mediated therapeutic strategies by testing the hypotheses that re-directing Mø polarization in vivo to the M2 phenotype suppresses dysferlinopathy.