Nocturnal hypoxemia dysregulates skeletal muscle protein homeostasis in COPD

Chronic obstructive pulmonary disease (COPD) is the 4th most common cause of death in the United States. Sarcopenia, or skeletal muscle loss, impacts up to 40% of COPD patients and is a major cause of morbidity and mortality. Despite the high significance, there are currently no effective therapies for sarcopenia in COPD due to limited understanding of the underlying mechanisms of skeletal muscle loss. However, we have identified that nocturnal hypoxemia, or low oxygen saturation during sleep and normal oxygen saturation while awake, is associated with sarcopenia in COPD patients. Nocturnal hypoxemia causes tissue-level hypoxia in the skeletal muscle, a condition we have termed prolonged intermittent hypoxia (PIH). Our preliminary and published data indicate that PIH upregulates hypoxia inducible factor (HIF)1α-dependent gene targets whose products dysregulate important muscle signaling and metabolic pathways to cause sarcopenia. These findings support the hypothesis that PIH induces HIF1α activity in skeletal muscle leading to sarcopenia in COPD. This hypothesis will be tested in vitro and in vivo in two specific AIMS. In Aim 1, we will determine the role of HIF1α on key aspects of skeletal muscle protein synthesis and homeostasis in response to PIH in vitro using loss/gain of HIF1α in murine myotubes and primary muscle cultures from murine and human models. In Aim 2, we will determine the role of HIF1α on key aspects of skeletal muscle protein synthesis, homeostasis and muscle function in response to PIH in live mice ± experimentally induced COPD ± PIH ± muscle specific deletion of HIF1α. Our proposal is innovative in concept because our novel model of PIH is a clinically relevant model that COPD patients routinely experience and is associated with sarcopenia. Our studies have the potential for broad application and high clinical relevance because PIH occurs in other pulmonary disorders associated with sarcopenia, such as interstitial lung disease or pulmonary hypertension. The proposed research is significant because this work may identify novel therapeutic targets in the treatment of sarcopenia in patients with COPD. This research will be performed in the laboratory of Dr. Dasarathy, Lerner Research Institute (LRI), Cleveland Clinic, and will be advised by experts in the field of muscle biology, lung biology, hypoxia, and COPD. Along with my mentor, my advisory panel has created a structured career development program, including formal coursework in molecular biology and translational research. My career goal is to build and lead an independent research program that will advance scientific knowledge and patient care in the field of COPD, hypoxia, and sarcopenia. Commitment to research, exceptional mentorship, and strong institutional support will allow me to become an independent and productive physician scientist.