The role of nNOS and PGC-1α in skeletal muscle cells

Abstract

Neuronal nitric oxide synthase (nNOS) and peroxisome proliferator activated receptor c co-activator 1a (PGC-1a) are two fundamental factors involved in the regulation of skeletal muscle cell metabolism. nNOS exists as several alternatively spliced variants, each having a specific pattern of subcellular localisation. Nitric oxide (NO) functions as a second messenger in signal transduction pathways that lead to the expression of metabolic genes involved in oxidative metabolism, vasodilatation and skeletal muscle contraction. PGC1a is a transcriptional coactivator and represents a master regulator of mitochondrial biogenesis by promoting the transcription of mitochondrial genes. PGC-1a can be induced during physical exercise, and it plays a key role in coordinating the oxidation of intracellular fatty acids with mitochondrial remodelling. Several lines of evidence demonstrate that NO could act as a key regulator of PGC-1a expression; however, the link between nNOS and PGC-1a in skeletal muscle remains only poorly understood. In this Commentary, we review important metabolic pathways that are governed by nNOS and PGC-1a, and aim to highlight how they might intersect and cooperatively regulate skeletal muscle mitochondrial and lipid energetic metabolism and contraction.

Altered glucose and lipid homeostasis in liver and adipose tissue pre-dispose inducible NOS knockout mice to insulin resistance

“…HF feeding to WT mice exhibited augmented serum lipids, altered insulin signaling, and expression of metabolically important enzymes/transcription factors31. iNOS KO mice exhibited altered expression of metabolically important genes (Figs 4 and 7), implying a regulatory role of iNOS/NO in glucose and lipid homeostasis, as reported for eNOS and nNOS KO mice33343536373839.…”

“…This might be probably due to non-stimulation of PGC-1α expression and its downstream PPAR-α is not regulated within 5 weeks of LFD feeding leading to mitochondrial dysfunction5051. It could be that PGC-1α up-regulation might not necessarily be dependent only on NO signaling pathways3952 or requires more time to affect the downstream pathways leading to change in the mitochondrial function. Mitochondrial OCR levels in KO mice were unaffected after feeding with 5 weeks LFD, thus suggesting mitochondrial dysfunction is not initiated, during the initial stages of IR.…”

“…Gene manipulation of endothelial NOS (eNOS) in mice has highlighted its importance in maintaining systemic glucose and lipids by regulating metabolism in three major metabolic organs (liver, skeletal muscle and adipose tissue)333435363738. On the other hand, studies on nNOS KO mice have demonstrated its crucial role in regulating metabolism of only peripheral organs excluding liver3339. Previous literature and data from hepatic, adipose tissue nitrite and eNOS, nNOS gene expressions associate tissue specific as well as systemic IR in KO mice, while no change in skeletal muscle nitrite and NOS expression correlated with their normal insulin signaling.…”

The role of AMP‐activated protein kinase in the expression of the dystrophin‐associated protein complex in skeletal muscle

“…Conversely, immunofluorescence measurements of nNOS detected significant elevations of the protein specifically at the sarco‐lemma. nNOS exists in 4 protein variants, including nNOSα, nNOSβ, nNOSγ, and nNOSμ (52). nNOSα and nNOSμ contain a postsynaptic density‐95/discs large/ zona occludens‐1 homology (PDZ) domain, which allows binding of the enzymes to the cell membrane.…”

Vitamin K2 Facilitating Inter-Organ Cross-Talk

“…PGC-1α seems to be instrumental in the modulation of mitochondrial biogenesis [5], and a further study established that PGC-1α elicited by physical activity seems to be crucial for oxidative metabolism in skeletal muscle fibres [6]. Furthermore, it was demonstrated that mitochondrial biogenesis induced by an enhancement in PGC-1α levels facilitates Wnt-mediated induction of osteoblastic differentiation of mesenchymal C3H10T1/2 cells [7].…”