Sarcopenia is an age-related syndrome characterized by a decrease in muscle mass and associated with a loss of strength and power, diminished functional performance, and increased disability and mortality. It is associated with several pathological condition including chronic disease and myopathy. The prevalence of sarcopenia is approximately 25% of the U.S. population over 70 years of age, thus greatly increased government healthcare expenditures by an expanding elderly population. This could be even more burden for the VA healthcare because the Veteran population is older than the general population. One of the mechanism involved in skeletal muscle sarcopenia is loss or senescence of stem cells resident in the skeletal muscle. Satellite cells are stem cells located beneath the basal lamina in close contact with the muscle fiber and are the major players in postnatal muscle growth and regeneration after injury. Thyroid hormones act as pleiotropic factors in various tissues during development by regulating genes involved in growth and differentiation, including skeletal muscle. We recently showed that thyroid hormone receptor ? (TR?) plays a crucial role in satellite cell proliferation and differentiation and skeletal muscle regeneration after injury. In this proposal we hypothesize that TR?, modulating skeletal muscle satellite cell senescence, is a key regulator in maintaining skeletal muscle mass during aging. Our preliminary observations demonstrate that a mice carrying a Resistance to Thyroid Hormone (RTH)-associate mutation for TR? has reduced muscle mass and strength and capability to regenerate after injury with aging. We are planning several studies devoted to extend our knowledge on molecular basis of thyroid hormones and TR? regulation of muscle stem cell senescence with aging. We will evaluate whether satellite-cell-intrinsic alterations may cause the loss in muscle and regenerative decline with age in mice with TR? mutations with a serial of in vivo transplantation strategies. We will analyze gene and protein expressions associated with transcription factors for quiescence, self-renewal, proliferation and differentiation of satellite cell and associated with chromatin remodeling by chromatin immunoprecipitation (ChIP) in vitro and in vivo animal model. Our goal is to identify therapeutic targets with the potential to promote satellite cell proliferation, differentiation, and response to injury, in conditions such as sarcopenia and skeletal muscle loss.
In sarcopenia, myogenesis is disrupted and glucose metabolism is altered. One of the crucial mechanism of sarcopenia is senescence of skeletal muscle satellite cells, which are the major players in skeletal muscle regeneration and maintenance. Understanding these processes may result in treatments that can be used for myopathy, skeletal muscle loss with aging and chronic disease, as well as enhancing recovery from skeletal muscle loss. Veteran population is older than the general population and hypothyroidism is common among elderly Veteran. Given the national trends in the Veteran population with respect to age, reported disability levels, it will be crucial studying the mechanism of skeletal muscle regeneration and maintenance during adult life and skeletal muscle metabolism. These studies will shed a new inside in the developing of sarcopenia with aging and new potential therapeutic targets, which the VA population will be the first to benefit.
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