α7β1 integrin regulation of skeletal muscle growth in response to mechanical stimulation

The α7β1 integrin has been proposed to serve as a mechanosensor and essential regulator of myofiber remodeling given its localization at the membrane and primary role in adhering the outer extracellular matrix to the inner actin cytoskeleton. However, additional work is necessary to affirm a primary role for the α7 integrin subunit in the regulation of skeletal muscle mass. The purpose of this dissertation was to 1) use gene expression profiling to reveal potential mechanisms by which the α7BX2 integrin can promote an increase in muscle mass post- eccentric exercise, 2) determine the extent to which the α7BX2 integrin contributes to an increase in muscle mass after chronic overload, and 3) determine the extent to which α7 integrin overexpression or integrin ligand (laminin-111, LM-111) binding can improve the anabolic response to loading in aged mice. Aim 1 used microarray analysis using RNA extracted from skeletal muscle of wild type (WT) or transgenic mice (MCK:α7BX2 integrin; α7Tg), under sedentary conditions and 3 hrs after an acute bout of downhill running. The results suggest that the α7β1 integrin initiates transcription of genes that allow for protection from stress and modulation of protein synthesis, both which may contribute to positive adaptations in skeletal muscle with mechanical stimulation. In Aim 2, WT and α7Tg mice were subjected to myotenectomy (MTE) of the gastrocnemius muscles and subsequent chronic mechanical loading (CML) for 1 day (1D) or 14 days (14D). The results suggest that the α7β1 integrin augments muscle mass and adaptation, and several changes may account for this observation, including a reduction in damage and stress, yes-associated protein (YAP) content, and increased phospho- 4E-BP1 on Ser65. In Aim 3, α7Tg overexpression was not sufficient to rescue the anabolic response to chronic loading in aged mice, yet injection of LM-111 significantly restored integrin localization at the membrane and the anabolic response to a mechanical stimulus. Overall, the studies in this dissertation suggest that the α7β1 integrin is an important regulator of muscle remodeling that leads to an increase in mass in response to mechanical strain, and that manipulation of the extracellular matrix within the microenvironment may provide a novel approach towards maintenance of mechanosensing and the anabolic response across the lifespan. These observations in mice provide impetus for assessment of the relationship between extracellular matrix protein composition and subsequent α7β1 integrin-mediated remodeling within human skeletal muscle