Disruption of the dystrophin complex causes the muscle membrane to become fragile and highly susceptible to damage. Muscular dystrophy is defined by ongoing muscle degeneration combined with insufficient regeneration. Although muscle regeneration is ongoing in these disorders, it is ineffective and fibrofatty infiltration ultimately replaces muscle resulting in muscle loss and weakness. We recently used a mouse model of Limb Girdle Muscular Dystrophy (LGMD), the Sgcg null mouse lacking y-sarcoglycan, to ask whether genetic modifier genes can alter the outcome in muscular dystrophy. We measured outcome using two quantitative assessments of muscle pathology, Evans blue dye uptake (dye uptake) to measure membrane fragility and leakiness and collagen deposition to reflect scarring in the muscle. We found that both membrane fragility and scarring were both strongly modified by Ltbp4, the gene encoding the latent TGFB binding protein. Genetic and molecular data support that cleavage of LTBP4 releases TGFB, making it more available to the cells within muscle. Enhanced TGFp signaling promotes both membrane disruption and scarring in muscular dystrophy. Similarly, an increase in full length LTBP4 is protective of both membrane leakiness and fibrosis. Based on studies performed with the related LTBP family members, we hypothesize that LTBP4 also binds myostatin. We posit a model for muscular dystrophy pathogenesis where LTBP4 cleavage releases both myostatin and TGFB, thereby promoting muscular dystrophy through increased scarring and decreased muscle growth.
In Aim 1, we will test this hypothesis by overexpressing the protective form of LTBP4 in myofibers and determining whether this reduces muscular dystrophy and downstream signaling.
In Aim 2, we will determine whether LTBP4 binds myostatin and the degree to which LTBP4 mediates its effects through myostatin using myostatin null mice.
In Aim 3, we will assess which proteases cleave LTBP4 since it is likely that both myostatin and LTBP4 are activated by the same proteases. The signaling aspects and protease experiments will be conducted in conjunction with Projects 2 and Project 3.

Public Health Relevance

The McNally laboratory recently discovered a gene, called Ltbp4, that can modify the outcome of muscular dystrophy. We will now test that genetic discovery using techniques to increase LTBP4 and to determine whether it exerts its effects through myostatin as well as TGFB.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Research Program Projects (P01)
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National Institute of Neurological Disorders and Stroke Initial Review Group (NSD)
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University of Chicago
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Molkentin, Jeffery D (2014) Letter by Molkentin regarding article, "The absence of evidence is not evidence of absence: the pitfalls of Cre Knock-Ins in the c-Kit Locus". Circ Res 115:e21-3
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