Physiologic Determinants of Ischemic Skeletal Muscle Pathophysiology

Abstract

Lower limb peripheral arterial occlusive disease (PAD) has major impacts on patient quality of life and, in its most severe form, carries a significant risk of mortality. The canonical approach to PAD research has been focused on the major contributions of the circulatory system. However, therapeutics that target vascular interventions have been largely unsuccessful in improving patient outcomes. This highlights the need for better understanding of the underlying nature of PAD pathology. The overall aim of this dissertation was to build a foundational understanding of the role of the lower limb skeletal muscle tissue microenvironment in ischemic outcomes. This dissertation ties together several independent studies that utilized in vitro, ex vivo, and in vivo experimental approaches in preclinical animal models and clinical manifestations of PAD. The overarching hypothesis is that physiologic determinants such as genetic background or diet can modify ischemic outcomes by impairing skeletal muscle resilience against acute ischemic injury or regenerative capacity during chronic ischemia. We found that in preclinical models of muscle ischemia, genetic background significantly affects pathologic outcomes and can be rescued by transduction of specific genes. We found that environmental factors such as a high fat diet can override genetic protection in a parental strain of mice that typically exhibits rapid recovery. We also found that human patients with the most severe form of PAD develop characteristic impairments to muscle oxidative capacity that is conserved in the resident myogenic progenitor cells. Lastly, we refined a model of experimental ischemia that uses isolated muscle to obtain highly detailed measurements of mechanical performance under ischemic conditions. We found that healthy skeletal muscle is robust to metabolic constraints, and that slow contracting oxidative muscles may be more resilient to acute ischemia than fast contracting glycolytic muscles. Together our observations indicate that skeletal muscle specific factors contribute directly to ischemic pathology and represent a potent target for therapeutic development.