Duchenne muscular dystrophy (DMD) is a devastating genetic muscle disorder. Augmenting the regeneration potential of endogenous muscle progenitor cells is one of the potential approaches to attenuate disease progression in DMD. Moreover, introduction of exogenous muscle stem cells can be used as an approach to restore dystrophin levels in DMD patients. However, transplantation of muscle stem cells into dystrophic muscles typically results in minimal engraftment which is attributed, at least in part, o the poor fusion of the introduced myogenic cells with injured myofibers. While the mechanisms of myoblast fusion remain less understood, enhancing fusion of endogenous or introduced myogenic cells has enormous potential for the development of novel cellular therapies for DMD patients. Ongoing studies in my laboratory have identified myeloid differentiation primary response gene 88 (Myd88), as a major positive regulator of myoblast fusion. Our preliminary studies have shown that levels of Myd88 are increased during muscle regeneration and upon induction of differentiation in cultured myoblasts. Genetic deletion of Myd88 specifically inhibits myoblast fusion without affecting their proliferation and differentiation. While our preliminary studies clearly demonstrate that Myd88-mediated signaling promotes myoblast fusion, it remains unknown whether augmenting the levels of Myd88 in myoblasts can stimulate myofiber regeneration and improve engraftment of introduced myoblasts in DMD. In this project, we have proposed to investigate the effects of myoblast-specific ablation and overexpression of Myd88 on disease progression in a preclinical mouse model of DMD. Our hypothesis and specific aims are:
AIM I : Investigate the effects of myoblast-specific deletion of Myd88 in myopathy of mdx mice. Hypothesis I: Myoblast-specific deletion of Myd88 will inhibit repair of injured myofibers and exaggerate myopathy in mdx mice.
AIM II : Investigate the effects of myoblast-specific overexpression of Myd88 in the pathogenesis of mdx mice. Hypothesis IIa: Overexpression of Myd88 in exogenous myoblasts (before transplantation) will improve their engraftment in dystrophic muscle of mdx mice; and Hypothesis IIb: Myoblast-specific transgenic overexpression of Myd88 will enhance myofiber regeneration and mitigate myopathy in mdx mice. Successful completion of this work will provide basis for considering Myd88 as therapeutic target in preclinical trials for patients with DMD. Furthermore, the project will provide me outstanding new training to achieve my goal of becoming a tenure-track faculty in an academic institution.
Duchenne muscular dystrophy (DMD) is the most prevalent form of muscular dystrophy which involves severe muscle-wasting, fibrosis, and premature death of afflicted individuals. We have identified Myd88 as a major regulator of myoblast fusion. We will investigate whether enhancing the levels of Myd88 in myoblasts can improve their fusion and improve regeneration of myofibers in preclinical models of DMD. Our proposed studies will provide strong basis whether Myd88 can be used as novel molecular target for treatment of DMD patients in future therapies.
|Hindi, Sajedah M; Sato, Shuichi; Xiong, Guangyan et al. (2018) TAK1 regulates skeletal muscle mass and mitochondrial function. JCI Insight 3:|
|Gallot, Yann S; Straughn, Alex R; Bohnert, Kyle R et al. (2018) MyD88 is required for satellite cell-mediated myofiber regeneration in dystrophin-deficient mdx mice. Hum Mol Genet 27:3449-3463|
|Hindi, Sajedah M; Shin, Jonghyun; Gallot, Yann S et al. (2017) MyD88 promotes myoblast fusion in a cell-autonomous manner. Nat Commun 8:1624|
|Hindi, Lubna; McMillan, Joseph D; Afroze, Dil et al. (2017) Isolation, Culturing, and Differentiation of Primary Myoblasts from Skeletal Muscle of Adult Mice. Bio Protoc 7:|
|Gallot, Yann Simon; Hindi, Sajedah M; Mann, Aman K et al. (2016) Isolation, Culture, and Staining of Single Myofibers. Bio Protoc 6:|
|Hindi, Sajedah M; Kumar, Ashok (2016) Toll-like receptor signalling in regenerative myogenesis: friend and foe. J Pathol 239:125-8|