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.

Public Health Relevance

We proposed to investigate the role of thyroid hormone receptor isoforms in adult skeletal muscle myogenesis and ectopic adipogenesis. We will try to identify possible mechanisms involved in satellite cell differentiation that can be used for a bettr understanding of diseases related with impaired adult myogenesis and ectopic intra-muscle adipogenesis, and can be applied to identify possible pharmaceutical target(s).

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Clinical Investigator Award (CIA) (K08)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Hyde, James F
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University of California Los Angeles
Internal Medicine/Medicine
Schools of Medicine
Los Angeles
United States
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Milanesi, Anna; Lee, Jang-Won; Kim, Nam-Ho et al. (2016) Thyroid Hormone Receptor α Plays an Essential Role in Male Skeletal Muscle Myoblast Proliferation, Differentiation, and Response to Injury. Endocrinology 157:4-15
Liu, Yan-Yun; Ayers, Stephen; Milanesi, Anna et al. (2015) Thyroid hormone receptor sumoylation is required for preadipocyte differentiation and proliferation. J Biol Chem 290:7402-15
Lee, Jang-Won; Kim, Nam-Ho; Milanesi, Anna (2014) Thyroid Hormone Signaling in Muscle Development, Repair and Metabolism. J Endocrinol Diabetes Obes 2:1046
Villani, Valentina; Milanesi, Anna; Sedrakyan, Sargis et al. (2014) Amniotic fluid stem cells prevent *-cell injury. Cytotherapy 16:41-55
Goodstein, Gelsey; Milanesi, Anna; Weinreb, Jane E (2014) Ketosis-prone type 2 diabetes in a veteran population. Diabetes Care 37:e74-5
Le, Karen; Milanesi, Anna; Weinreb, Jane E (2014) How long should we continue prednisone after abiraterone discontinuation? Endocr Pract 20:992-3