Thyroid Hormone Receptor Isoforms in Skeletal Muscle

描述（由申请人提供）：骨骼肌中的干细胞在出生后的肌肉生长和损伤后的再生中起重要作用。有人提出，骨骼肌卫星细胞的命运可以从肌生成转变为脂肪生成，因此在一些病理情况下，如肌病、2型糖尿病、肥胖和年龄相关性肌肉减少症，会导致肌内脂肪异位积累。在这一建议中，我们假设甲状腺激素受体（TR）异构体在体内和体外调节骨骼肌卫星细胞的承诺和细胞命运规范。我们的初步观察结果表明，甲状腺激素受体（TR）在体外和体内卫星细胞的增殖以及向体外肌源性和脂肪源性细胞谱系的分化中都起着重要作用。此外，甲状腺激素受体（TR）在成脂分化中起作用，抑制其表达不会损害卫星细胞的增殖和分化

DESCRIPTION (provided by applicant): Stem cells resident in the skeletal muscle play an important role in postnatal muscle growth and regeneration after injury. It has been proposed that skeletal muscle satellite cell fate can be switched from myogenesis to adipogenesis and for this reason contribute to ectopic intra-muscle fat accumulation in several pathological condition such us myopathy, type 2 diabetes, obesity, and age-related sarcopenia. In this proposal we hypothesize that thyroid hormone receptor (TR) isoforms modulate skeletal muscle satellite cell commitment and cell fate specification in vitro and in vivo. Our preliminary observations demonstrate that thyroid hormone receptor ¿ (TR¿) has an important role both in proliferation of satellite cells in vitro and in vivo and in their differentiation to myogenic and adipogenic cell lineages in vitro. In addition thyroid hormone receptor ¿ (TR¿) plays a role in adipogenic differentiation and knocking down this expression does not impair satellite cells proliferation and differentiation into functional myofibers. To confirm and further develop these preliminary data, we plan to conduct in vitro study on primary muscle satellite cells derived from mice carrying a Resistance to Thyroid Hormone (RTH)-associate mutation for TR¿ and TR¿. We are planning several studies devoted to extend our knowledge on molecular basis of TR isoform regulation of muscle stem cell lineage allocation. We will analyze gene and protein expressions associated with transcription factors for self-renewal and differentiation of satellite cell and associated wih Wnt signaling pathway. Subsequently we will evaluate the in vivo differentiation potential of muscle satellite cell carrying a TR ¿ or ¿ mutation after transplantation into preinjured muscles. In addition, we will investigate the role of TR ¿ and ¿ in skeletal muscle response to injury by utilizing both genetic and pharmacologic tools. The work proposed in this grant will provide insight into skeletal muscle stem cell fate allocation and intra-muscle ectopic adipogenesis and the possible role of TR isoforms in modulating this process. The K08 application proposed a detailed, comprehensive training plan that will allow the applicant to pursue studies related to her research and career goals. An outstanding team of mentors will directly oversee the research training in various angles and all the aspects of research in progress. The ultimate goal is for the applicant to leverage the data obtained during this grant period into a successful R01 application. This will then allow the applicant to become an independently-funded physician-scientist in the field of endocrinology bridging stem cell research.