Leptin is a physiological regulator of skeletal muscle angiogenesis and is locally produced by PDGFRα and PDGFRβ expressing perivascular cells

Abstract

Skeletal muscle capillarity is characteristically reduced in mature leptin receptor-deficient (Lepr^db) mice, which has been attributed to the capillary loss that occurs secondary to metabolic dysfunction. Despite wide recognition of leptin as a pro-angiogenic molecule, the contribution of this adipokine has largely been overlooked in peripheral tissues. Moreover, prior documentation of leptin production within skeletal muscle indicates a potential paracrine role in maintaining local tissue homeostasis. Thus, we hypothesized that leptin is a physiological local paracrine regulator of skeletal muscle angiogenesis and that its production may be modulated by nutrient availability. Lepr^db mice exhibited impaired angiogenesis during normal developmental maturation of skeletal myocytes, corresponding with an inability to increase vascular endothelial growth factor-A (VEGFA) mRNA and protein levels between 4 and 13 weeks. In cultured murine and human skeletal myocytes, recombinant leptin increased VEGFA mRNA levels. Leptin mRNA was detectable in skeletal muscle, increasing with prolonged high-fat feeding in mice, and with adiposity in human subjects. Platelet-derived growth factor receptor (PDGFR)α− and PDGFRβ− expressing perivascular cell populations were identified as leptin producing within skeletal muscle of mice and humans. Furthermore, in response to 2 weeks of high-fat feeding, PDGFRβ+ but not PDGFRα+ cells increased leptin production. We conclude that leptin is a physiological regulator of the capillary network in skeletal muscle and stimulates VEGFA production by skeletal myocytes. PDGFRβ expressing perivascular cells exhibit the capacity to act as local "nutrient-sensors" that couple nutrient status to leptin production in skeletal muscle.