Molecular Coordination of Skeletal Muscle Capillary Remodeling in Obesity: Implications for Metabolic Homeostasis and Disease

Considerable effort has been directed towards the development of preventative and therapeutic strategies against obesity and its clinical sequalae that now pose a significant public health and economic burden on healthcare systems worldwide. The skeletal muscle capillary network has emerged as a critical determinant of metabolic homeostasis and structural remodelling of this network is now widely accepted to contribute to the pathogenesis of obesity. However, the regulation of skeletal muscle capillary remodelling in obesity remains controversial and largely unexplored. The purpose of the current dissertation was to define intrinsic molecular mechanisms that govern these skeletal muscle capillary remodelling responses in obesity. Administration of a 16-week high-fat (HF) diet was associated with and expansion (angiogenesis) of the skeletal muscle capillary network and promoted the expression of pro-angiogenic factors including leptin and vascular endothelial growth factor-A (VEGF-A). To investigate the potential involvement of anti-angiogenic factors in mediating the capillary remodelling response in obesity, I investigated the role of forkhead box O (FoxO) transcription factors that are potent repressors of skeletal muscle angiogenesis and have previously been implicated in the progression of metabolic disorders. In transgenic mice that have an endothelial cell directed depletion of FoxO proteins (Foxo mice), I demonstrated enhanced angiogenesis after 16-weeks of HF diet, which was associated with the preservation of peripheral insulin sensitivity. Together, these findings demonstrated that angiogenesis is a physiological adaptation to obesity that is governed by the net-influence of pro- and anti-angiogenic molecular factors. Finally, to determine whether the positive influence of obesity on the skeletal muscle capillary network was beneficial in a pathological context, HF-preconditioned mice were subjected to a pre-clinical model of peripheral artery disease, a condition characterized by reduced blood flow (ischemia) to the lower limbs. HF-preconditioning elicited an overall increase in capillary perfusion, which was associated with enhanced microvascular remodelling, blood flow recovery and tissue regeneration following the onset of ischemia, highlighting the potential benefit of vasculo-centric therapies against the clinical progression of obesity. Overall, these findings demonstrate that angiogenesis is a physiological adaptation that preserves metabolic homeostasis and provides mechanistic insight into the coordination of skeletal muscle capillary in obesity.