Duchenne muscular dystrophy (DMD) is a lethal, muscle-wasting disorder that is caused by mutations in the dystrophin gene. Current treatment options for DMD patients target secondary disease processes such as inflammation that can accelerate disease progression. However, therapies that employ immuno-suppressants and anabolic steroids commonly result in undesirable side effects with chronic use. Therefore, studies aimed at understanding the cellular and molecular mechanisms that regulate interactions between muscle and the immune system are needed. The investigation we propose may contribute to the development of new therapeutic modalities that target inflammation with reduced side effects. The overall objective of the investigation proposed here is to use genetic mouse models of DMD to examine the role of regulatory T cells (Tregs) on myofiber injury and regeneration during muscular dystrophy. We specifically aim to assess whether Tregs regulate the development and progression of muscular dystrophy (aim 1). In addition, we aim to test the hypothesis that regulatory T cells secrete factors that promote muscle repair by promoting M2 polarization of macrophages or directly modulating muscle regeneration (aim 2). To determine the physiological relevance of the Tregs in vivo we propose using various mouse models that will examine the role of Tregs on muscle injury, inflammation and regeneration. Specifically, a combination of Treg depletion and adoptive transfer assays will be employed to examine the role of Tregs in regulating the course of dystrophinopathy. Because the interpretation of in vivo studies may be complicated by the numerous physiological factors that regulate muscle regeneration, we will use in vitro assays to test the ability of Tregs to directly modulate muscle regeneration using assays that measure muscle cell proliferation and differentiation. The findings of this investigation may shed light on the inflammation-mediated, pathophysiological mechanisms that regulate the development and progression of muscular dystrophy. Elucidating the potential role of Tregs in muscular dystrophy and the mechanism of Treg-mediated amelioration in this setting may result in the advancement of treatments that specifically inhibit cytotoxic immune cell interactions with muscle.

Public Health Relevance

Duchenne muscular dystrophy (DMD) is caused by mutation of the dystrophin gene, causing wide spread muscle death and an immune response to injured muscle that further exacerbates muscle degeneration. Currently, no cure for DMD exists and patients afflicted by this disease die by the 2nd-3rd decade of life. The current study will explor the function of regulatory T cells that suppress immune responses, and aims to discover novel pathways and molecules that can be therapeutically targeted to treat Duchenne muscular dystrophy.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Postdoctoral Individual National Research Service Award (F32)
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Special Emphasis Panel (ZRG1)
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Boyce, Amanda T
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University of California San Francisco
Internal Medicine/Medicine
Schools of Medicine
San Francisco
United States
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Villalta, S Armando; Rosenthal, Wendy; Martinez, Leonel et al. (2014) Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Sci Transl Med 6:258ra142