Severine Groh, PhD

Role of Sarcospan in Adipogenesis

The matrisome comprising the core proteins that form the extracellular matrix (ECM) and the ECM-associated components plays a crucial role in human health. Interactions between the ECM and its membrane receptors such as integrin receptors and dystroglycan are particularly significant for the formation, maintenance, and functions of tissues by influencing cell behavior and mediating physiological processes. Alteration in the composition and structure of theECM have been documented in a variety of muscle dystrophies and metabolic disorders. Sarcospan (sspn) is a 25kDa scaffolding protein shown to stabilize dystroglycan and integrin receptors in muscle tissues. Sarcospan expression is strongly reduced at the sarcolemma of patients with muscular dystrophy. Its overexpression in the muscles of the Mdx mouse, a mouse model for Duchenne Muscular Dystrophy, alleviates the dystrophic hallmarks, suggesting that sarcospan may be a therapeutic candidate for muscular dystrophy and perhaps non-muscle disorders associated with aberrant ECM-cell connections. The functional role of sspn in non-skeletal muscle tissues, healthy and diseased remains poorly understood. Our data indicate that sspn is well expressed in mature white adipocytes. White adipocytes are key regulators of fat storage and metabolic homeostasis. Aberrations in white adipocyte physiology canlead to devastating consequences including obesity-related disorders. Adipocytes differentiation from preadipocytes depend on a well-orchestrated series of signaling mechanisms concomitant with a profound integrin-mediated reorganization of the ECM and the cytoskeleton and targeted gene expression relevant to lipid metabolism.

Based on our preliminary findings indicating that sarcospan deficient have increased adiposity with adipocyte hypertrophy, altered glucose homeostasis and insulin resistance, we hypothesize that sarcospan is a critical regulator of late adipocyte differentiation by (1) stabilizing the integrin-mediated interaction between the cell membrane and the ECM and (2) influencing intracellular lipid metabolism signaling pathways. To test this hypothesis, we will take advantage of RNAi silencing approaches in a well characterized in vitro model of adipocyte differentiation and examine downstream consequences on (1) kinetics of differentiation, (2) expression and localization of integrin complexes, and (3) gene expression of fundamental adipogenic markers and lipid metabolism. We anticipate that the success of these studies will provide key insights into the molecular underpinnings of adipocyte differentiation. Anticipated data have the potential of enhancing our ability to target molecular factors in disordersassociated with altered adiposity. Our studies will be well integrated into an educational curriculum for undergraduatesat Delta State University, MS, comprising an inquiry-based research experience. The success of the program will be evaluated by well- established metrics. In the long-term, we anticipate that the success of this program will boost student engagement with limited prior research experience and propel them to biomedical careers.