Alpha7 Integrin-Mediated Hypertrophic Signaling and Growth in Skeletal Muscle

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DESCRIPTION (provided by applicant): It is estimated that 19% of the population in the US will be older than 65 years by 2030. The majority of these individuals will lose mobility and succumb to disability as a result of sarcopenia, or the decline in muscle mass and function that occurs with age. Current treatment for sarcopenia includes growth hormone and androgenic compounds that inconsistently ameliorate muscle loss. The long-term goal of our laboratory is to develop novel and effective interventions that can counteract muscle loss with aging. The specific objective of this proposal is determine the extent to which the α7 integrin is an intrinsi modulator of load-induced skeletal muscle growth and assess whether restoration of α7 integrin protein can prevent anabolic resistance to mechanical loading in aged skeletal muscle. The α7 integrin is a transmembrane adhesion protein that can link the actin cytoskeleton inside muscle fibers to the extracellular matrix (ECM), specifically laminin. Our recently published studies have clearly demonstrated that transgenic overexpression of the α7 integrin can enhance new fiber synthesis and growth in young muscle following eccentric exercise. To our knowledge, no studies have been conducted to determine whether the α7 integrin is an intrinsic modulator of load-induced muscle growth or the extent to which α7 integrin function is decreased with age, providing the underlying basis for anabolic resistance to mechanical loading. Our central hypothesis is that the α7 integrin is an essential mechanotransducer in skeletal muscle and that restoration of integrin expression can overcome anabolic resistance to mechanical loading with age. Thus, this work seeks to 1) determine the extent to which the α7 integrin is an intrinsic regulator of load- induced hypertrophic signaling and growth in skeletal muscle, and 2) determine the extent to which loss of α7 integrin protein expression is the basis for anabolic resistance to mechanical loading in aged skeletal muscle. This work is highly innovative because it is the first to evaluate the α7 integrin as an underlying basis of muscle atrophy with age and incorporates a novel strategy for countering anabolic resistance. The proposed work is significant because it is expected to establish the α7 integrin as a potential therapeutic target fr the stimulation of muscle growth in an aged microenvironment. Ultimately, such knowledge has the potential to initiate a continuum of research that will prevent and treat sarcopenia.