PGC-1α Induces SPP1 to Activate Macrophages and Orchestrate Functional Angiogenesis in Skeletal Muscle

Abstract

Rationale Mechanisms of angiogenesis in skeletal muscle remain poorly understood. Efforts to induce physiological angiogenesis hold promise for the treatment of diabetic microvascular disease and Peripheral Artery Disease (PAD), but are hindered by the complexity of physiological angiogenesis and by the poor angiogenic response of aged and diabetic patients. To date, the best therapy for diabetic vascular disease remains exercise, often a challenging option for patients with leg pain. PGC-1α, a powerful regulator of metabolism, mediates exercise-induced angiogenesis in skeletal muscle. Objective To test if, and how, PGC-1α can induce functional angiogenesis in adult skeletal muscle. Methods and Results We show here that muscle PGC-1α robustly induces functional angiogenesis in adult, aged, and diabetic mice. The process involves the orchestration of numerous cell types, and leads to patent, non-leaky, properly organized, and functional nascent vessels. These findings contrast sharply with the disorganized vasculature elicited by induction of VEGF alone. Bioinformatic analyses revealed that PGC-1α induces the secretion of secreted phosphoprotein 1 (SPP1), and the recruitment of macrophages. SPP1 stimulates macrophages to secrete monocyte chemoattractant protein-1 (MCP-1), which then activates adjacent endothelial cells, pericytes, and smooth muscle cells. In contrast, induction of PGC-1α in SPP1 −/− mice leads to immature capillarization and blunted arteriolarization. Finally, adenoviral delivery of PGC-1α into skeletal muscle of either young or old and diabetic mice improved the recovery of blood flow in the murine hind-limb ischemia model of PAD. Conclusions PGC-1α drives functional angiogenesis in skeletal muscle and likely recapitulates the complex physiological angiogenesis elicited by exercise.

Molecular networks in skeletal muscle plasticity

“…PGC-1 plays its role in the control of energy metabolism by serving as master regulator for coordinated programs of gene expression by a multitude of transcription factors. Specific variants of PGC-1α are induced by a variety of physiological cues (discussed below) increasing muscle tissue mitochondrial content and capillarity (Rowe et al, 2014). This is not the case for PGC-1β, which is assumed to regulate basal mitochondrial function (see Villena, 2015).…”

PGC-1α, glucose metabolism and type 2 diabetes mellitus

“…Moreover, aberrant DNA methylation in the PGC-1α promoter sequence also contributes to impaired glucose tolerance by influencing the expression of PGC-1α and GLUT4 in skeletal muscle (Zeng et al 2013). In addition, PGC-1α has been shown to directly induce angiogenesis in skeletal muscle by enhancing the delivery of oxygen and glucose (Arany et al 2008, Rowe et al 2014, although not in all studies (Sawada et al 2014). Thus, PGC-1α-mediated increase in skeletal muscle glucose uptake is probably due to the modulation of blood flow.…”

Metabolism in cancer metastasis

“…18 PGC-1a may act as an inducer of osteopontin expression, likely through synergism with ERRa. 55,56 It is possible that it may exert its prometastatic effect through osteopontin.…”