Distinct responses to hypoxia in striated muscle

PROJECT SUMMARY The cellular response to hypoxia is highly conserved yet is strikingly different between mammalian cell types. Even within striated muscle, which represents over 40% of human body mass, the response to hypoxia is distinct between skeletal and cardiac muscles. Our group is interested in understanding how these striated muscle cells respond to hypoxia and how hypoxia-mediated changes in muscle metabolism contribute to muscle-specific outcomes and the integrative response to low oxygen. In the proposed project period, we will investigate 1) the mechanisms of hypoxia sensing and signaling in response to acute and chronic hypoxia; and 2) the integrated systems physiology by which striated muscles interact in settings of low oxygen. We will investigate these mechanisms in three types of striated muscle that we and others have previously demonstrated have distinct responses to hypoxia- skeletal, right ventricular (RV) and left (LV) cardiac muscle. Our approach will develop and utilize new transgenic mouse models, use novel tools to quantify hypoxia, and capitalize on integrative ex vivo approaches to dissect systems-level responses to low oxygen. A multitude of human conditions and environmental stimuli impart changes in local or systemic oxygen levels, yet the specific mechanisms of hypoxia signaling and their integration across systems remains unclear. The proposed integrative studies from multiple muscle cell types will increase our mechanistic understanding of the basic molecular and physiological responses to low oxygen.