Project Two: Modifying Heart and Skeletal Muscle in Muscular Dystrophy

Project Lead: Elizabeth McNally, PhD, Northwestern University
Co-Investigator: Melissa Spencer, PhD, University of California, Los Angeles

Project 2 of this Wellstone Center has been studying modifiers of muscular dystrophy and its associated cardiomyopathy. Through the first funding period of this Wellstone Center (2010-2015), we evaluated latent TGF-b binding protein 4 (LTBP4) as a modifier of muscular dystrophy, discovering human genetic variation that correlated with prolonged ambulation in Duchenne Muscular Dystrophy (DMD). The Ltbp4 modifier data from mice demonstrated that LTBP4’s hinge is critical for stabilizing latent TGFb and myostatin and preventing their release and activity. From this work, we are advancing anti-LTBP4 antibodies as a potential biological agent to treat DMD. We identified a second modifier, Anxa6, encoding annexin A6. Using high resolution, real-time microscopy we found that annexin A6 functions as a mediator of membrane repair. We also uncovered a critical interaction between glucocorticoid steroids and annexin A6, demonstrating that intermittent low-dose glucocorticoid steroids promote membrane resealing, in part, by upregulating annexin A6. Glucocorticoid steroids are a pharmacologic modifier of DMD, but their mechanisms of action in DMD are incompletely understood. In mouse models of muscular dystrophy, we found that intermittent low dose steroids enhanced muscle repair and muscle performance without the same adverse side effects elicited from daily steroids. Furthermore, we found that intermittent steroid use improved strength and function in several mouse models of Limb Girdle Muscular Dystrophy, prompting a pilot clinical trial in patients with muscular dystrophy types not normally treated with steroids. We will now focus on defining how steroid use alters muscle inflammatory cells and how this is reflected in serum and cytokine profiles. These studies are specifically designed to translate into the human setting. We will also explore a novel compound that leads to CaMK activation, a key feature seen after intermittent steroid use. We plan to test models for Duchenne Muscular Dystrophy as well as Limb Girdle Muscular Dystrophy. In the last aim, we will test a putative new modifier for the heart in muscular dystrophy, as this modifier is expected to promote similar metabolic shifts seen in muscle after intermittent steroid use. Overall, these experiments are designed to identify dosing strategies, pharmacodynamic biomarkers, and novel treatments that can be used in muscular dystrophy patients on their own or as adjuncts to gene therapy. The outcomes from these experiments will be used in translating these findings to patients with multiple forms of muscular dystrophy. This Project is conducted jointly with investigators from Northwestern and UCLA with collaboration from investigators and core facilities at the University of Florida.

Project Three

Understanding and Improving Therapies for the Muscular Dystrophies through Noninvasive Biomarkers