The muscular dystrophies are inherited disorders that largely affect striated muscle tissue resulting in progressive muscle weakness, wasting, and in many instances, premature death. Many characterized mutations in humans that cause muscular dystrophy (MD) result from alterations in structural attachment proteins that affix the underlying contractile proteins to the basal lamina, providing rigidity to the skeletal muscle cell membrane (sarcolemma). Loss of select attachment proteins in the dystrophin-glycoprotein complex (DGC) permits contraction-induced membrane tears and influx of calcium that causes cellular degeneration and necrosis of muscle fibers. During this necrotic process cytokines, chemokines and growth factors are released as part of the inflammatory and repair process, although induction of fibrosis and scarring are an unwanted side effect that worsens disease. One prominent cytokine is transforming growth factor-? (TGF?) that serves a master regulator of the fibrotic response and worsening of muscle pathology in MD. While fibroblasts are directly regulated by TGF?, no one has yet to examine the function of the fibroblast in skeletal muscle directly in vivo, as a mediator or fibrosis and muscular dystrophy. Here we generated a unique genetic model in the mouse that will selectively modulate the activity of the cardiac and skeletal muscle fibroblast in vivo and in dystrophic mouse models of disease. Thus, here we will test the novel hypothesis that myofibroblasts play a selective role in mediating fibrosis and tissue remodeling in heart and skeletal muscle in response to cellular dropout from MD, while resident myofibers and cardiomyocytes in their respective tissues underlie physiologic ECM / collagen production and basal lamina production during development and as part of ongoing homeostasis. The application has 2 comprehensive specific aims: 1) To genetically parse the role of myofibroblasts in skeletal muscle and heart during MD in the mouse, 2) To examine how TGF?, SMAD2/3 and p38? signaling mediate disease in MD through the myofibroblast in vivo. The application will attempt to definitively address the function of the activated fibroblast (myofibroblast) in muscle during MD disease onset and progression. It will also attempt to elucidate the importance of TGF? signaling in mediating myofibroblast formation and disease activity in vivo, as both canonical and non- canonical pathways will be genetically dissected.
Accumulation of fibrotic material in the skeletal muscles of muscular dystrophy patients is thought to be a determinant of progressive functional decline, lack of regenerative capacity, as well as a contributor to debilitating contractures. New therapies directed at limiting the fibrotic response are desperately needed in this disease. Understanding the molecular mechanisms that lead to skeletal muscle fibrosis in muscular dystrophy is of the utmost importance. This Project will investigate the signaling pathways that mediate tissue fibrosis in muscular dystrophy from within the fibroblast itself, with the goal of identifying novel pharmacologic treatments.
| Kwong, Jennifer Q; Huo, Jiuzhou; Bround, Michael J et al. (2018) The mitochondrial calcium uniporter underlies metabolic fuel preference in skeletal muscle. JCI Insight 3: |
