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 ?7 integrin is an intrinsi modulator of load-induced skeletal muscle growth and assess whether restoration of ?7 integrin protein can prevent anabolic resistance to mechanical loading in aged skeletal muscle. The ?7 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 ?7 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 ?7 integrin is an intrinsic modulator of load-induced muscle growth or the extent to which ?7 integrin function is decreased with age, providing the underlying basis for anabolic resistance to mechanical loading. Our central hypothesis is that the ?7 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 ?7 integrin is an intrinsic regulator of load- induced hypertrophic signaling and growth in skeletal muscle, and 2) determine the extent to which loss of ?7 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 ?7 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 ?7 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.
It is estimated that 19% of the population in the US will be older than 65 years by 2030, and the majority of these individuals will lose mobility or succumb to disability as a result of sarcopenia, or the decline in muscle mass and function that occurs with age. The proposed studies will utilize both in vitro and in vivo approaches to assess an intrinsic role for a7 integrin in load-induced skeletal muscle growth and determine the extent to which restoration of this protein can combat anabolic resistance to mechanical loading with age. This project is highly relevant to the mission of NIH and public health because it will identify the a7 integrin as a potential target in the prevention and treatment of sarcopenia in our growing aged population.
|Mahmassani, Ziad S; Son, Kook; Pincu, Yair et al. (2017) ?7?1Integrin regulation of gene transcription in skeletal muscle following an acute bout of eccentric exercise. Am J Physiol Cell Physiol 312:C638-C650|
|Garg, Koyal; Boppart, Marni D (2016) Influence of exercise and aging on extracellular matrix composition in the skeletal muscle stem cell niche. J Appl Physiol (1985) 121:1053-1058|