Natriuretic peptides enhance the oxidative capacity of human skeletal muscle

Abstract

Cardiac natriuretic peptides (NP) are major activators of human fat cell lipolysis and have recently been shown to control brown fat thermogenesis. Here, we investigated the physiological role of NP on the oxidative metabolism of human skeletal muscle. NP receptor type A (NPRA) gene expression was positively correlated to mRNA levels of PPARγ coactivator-1α (PGC1A) and several oxidative phosphorylation (OXPHOS) genes in human skeletal muscle. Further, the expression of NPRA, PGC1A, and OXPHOS genes was coordinately upregulated in response to aerobic exercise training in human skeletal muscle. In human myotubes, NP induced PGC-1α and mitochondrial OXPHOS gene expression in a cyclic GMP-dependent manner. NP treatment increased OXPHOS protein expression, fat oxidation, and maximal respiration independent of substantial changes in mitochondrial proliferation and mass. Treatment of myotubes with NP recapitulated the effect of exercise training on muscle fat oxidative capacity in vivo. Collectively, these data show that activation of NP signaling in human skeletal muscle enhances mitochondrial oxidative metabolism and fat oxidation. We propose that NP could contribute to exercise training-induced improvement in skeletal muscle fat oxidative capacity in humans. IntroductionThe cardiac hormones, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), play a major role in the regulation of fluid homeostasis and cardiac physiology (1). Natriuretic peptidemediated (NP-mediated) biological responses are largely mediated through cyclic GMP (cGMP) produced by the guanylyl cyclase domain of NP receptor type A (NPRA) (2). Although classically considered as cardiovascular hormones, we have shown that NP display a potent lipolytic effect in human adipocytes (3). They promote a rapid and sustained rise of intracellular cGMP that activates a cGMP-dependent protein kinase, PRKG1, which then phosphorylates perilipin 1 and hormone-sensitive lipase, necessary steps to initiate lipolysis (4). The potent lipolytic effect of NP is restricted to primates. In contrast, murine adipocytes exhibit a predominance of the clearance receptor NP receptor type C (NPR-C) and a very low expression of the biologically active NPRA (5). Interestingly, the lipolytic effect of NP is fully rescued in adipocytes of NPR-C (also known as Npr3) knockout mice. Moreover, NP induce a "browning" of human white adipocytes (6). This finding may be physiologically relevant considering the presence of functional brown fat in humans (7). Together, these studies suggest that NP plays a potent metabolic role in human adipose tissue. Recent data suggest that mice overexpressing Nppb and Prkg1 are protected from high-fat diet-induced obesity and insulin resistance and show increased energy expenditure (8). This phenotype could be explained by significant changes in skeletal muscle fat oxidative capacity. The physiological relevance and molecular mechanisms of this finding have yet to be addressed in humans. In this study,

Musclin is an activity-stimulated myokine that enhances physical endurance

“…Cardiac NPs are increasingly recognized as hormones with a wide spectrum of targets: In addition to traditional targets of vasculature and kidney, recently their effects on skeletal muscle mitochondrial biogenesis, angiogenesis, lipolysis, and adipose tissue remodeling (browning) have been reported (27)(28)(29)32). Although the present study focuses on one aspect of this signaling network, intramuscular cGMP signaling and mitochondrial biogenesis, it is possible that other cardiac NP signaling targets are similarly affected.…”

“…NP/cGMP signaling is increasingly recognized as a key regulator of metabolic homeostasis, including effects on skeletal muscle mitochondrial biogenesis and oxidative phosphorylation potential (27)(28)(29). Maximal aerobic capacity (V · O 2max )…”

Steep, coincident, and concordant clines in mitochondrial and nuclear‐encoded genes in a hybrid zone between subspecies of Atlantic killifish, Fundulus heteroclitus

“…Atrial natriuretic peptide is a hormone involved in osmoregulation that also has effects on aerobic metabolism in skeletal muscle (Engeli et al. 2012). These data suggest that patterns of genetic variation at these three loci might, at least in part, be shaped by endogenous selection against hybrids due to similar forces to those acting on the mtDNA clines.…”

Randomized Trial of the Effects of Insulin and Metformin on Myocardial Injury and Stress in Diabetes Mellitus: A Post Hoc Exploratory Analysis

“…In contrast, observational and Mendelian randomization studies suggest modest elevations in NPs protect against the development of T2DM 15, 16. In addition to their role in promoting natriuresis, diuresis, and blood pressure, NPs have a number of favorable metabolic effects, including increased lipolysis and activation of brown fat 17, 18, 19. Because of the associations between these cardiac biomarkers, glucose metabolism, and cardiovascular risk in patients with T2DM, we hypothesized that different strategies for glucose control might lead to clinically relevant changes in these markers of cardiac injury and cardiac stress.…”