Physiology of Respiratory Muscle Micromechanics

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DESCRIPTION (provided by applicant): Muscular dystrophy pathogenesis results from a broken mechanical and/or signaling linkage between the cytoskeleton and the extracellular matrix. In the first funding period of this grant we focused on determining the alteration in the mechanical, structural and functional integrity in skeletal muscles of specific models of muscular dystrophies. In the upcoming period of this project our objective is to understand the mechanisms involved with possible aberrant activation of pro-inflammatory signaling pathways in the respiratory pump of specific mouse models of muscular dystrophy. We will use the 2 complementary mouse models of muscular dystrophy, the mdx and alpha? integrin null mouse. Our specific aims are: Specific Aim # 1: To evaluate the role of the small GTPase proteins of Rho family such as RhoA, Racl and cdc42 in the mechanical stretch-induced signal transduction in normal skeletal muscles. Hypothesis 1: The small GTPase proteins RhoA, Racl and Cdc42 are involved in mechanical signal transduction in the diaphragm; each of these proteins has a distinct signaling role, which may depend on the direction of applied mechanical stress. Each of the proteins is involved in the initiation of a specific signal transduction pathway that affects the proliferation, differentiation and the gene expression in skeletal muscle cells. Specific Aim # 2; To examine whether mechanical stretch-induced activation of mechanosensitive transcription factors such as AP-1, C/EBP, NFKB and the activity of the Rho family GTPases are altered in muscle fibers lacking either dystrophin or a7 integrin Hypothesis 2: Mechanical stretching of skeletal muscles from dystrophic mice leads to aberrant activation of MAP kinases and mechanosensitive transcription factors, possibly through the anomalous regulation ofGTP binding proteins of Rho family. Specific Aim # 3: To test whether loss of either dystrophin or a7 integrin results in the activation of mechanosensitive transduction pathways leading to altered expression of muscle wasting cytokines such as TNF-a, IL-1p and proteases such as matrix metalloproteinase MMP9. Hypothesis 3: Mechanical stressinduced activation ofNF-KB and AP-1 in skeletal muscle of the mdx, and alpha7 integrin null mice may lead to an augmented level of muscle wasting cytokines and tissue degrading proteases. Higher activation of these proinflammatory molecules could lead to loss of structural integrity and contractile dysfunction in these dystrophic mice. Specific Aim # 4; To determine the role of mechanosensitive transcription factors NF-KB, C/EBP and AP-1 on the pathogenesis of muscular degeneration in mdx and a7 integrin null mice. Hypothesis 4: Inhibition of NF-KB and/or AP-1 will reduce the expression of inflammatory genes such as TNF-a, IL-6, IL-1B and MMPs, and therefore may reduce loss of structural integrity and cause possible gain in function in skeletal muscles of the mdx, and the alpha7 integrin null mice. The completion of these aims will significantly contribute to the fundamental understanding of mechanical signal transduction in the respiratory pump.