Nitric Oxide in Skeletal Muscle: Role on Mitochondrial Biogenesis and Function

Abstract

Nitric oxide (NO) has been implicated in several cellular processes as a signaling molecule and also as a source of reactive nitrogen species (RNS). NO is produced by three isoenzymes called nitric oxide synthases (NOS), all present in skeletal muscle. While neuronal NOS (nNOS) and endothelial NOS (eNOS) are isoforms constitutively expressed, inducible NOS (iNOS) is mainly expressed during inflammatory responses. Recent studies have demonstrated that NO is also involved in the mitochondrial biogenesis pathway, having PGC-1α as the main signaling molecule. Increased NO synthesis has been demonstrated in the sarcolemma of skeletal muscle fiber and NO can also reversibly inhibit cytochrome c oxidase (Complex IV of the respiratory chain). Investigation on cultured skeletal myotubes treated with NO donors, NO precursors or NOS inhibitors have also showed a bimodal effect of NO that depends on the concentration used. The present review will discuss the new insights on NO roles on mitochondrial biogenesis and function in skeletal muscle. We will also focus on potential therapeutic strategies based on NO precursors or analogs to treat patients with myopathies and mitochondrial deficiency.

From physical inactivity to immobilization: Dissecting the role of oxidative stress in skeletal muscle insulin resistance and atrophy

“…has also been found in the sarcoplasm and the Golgi apparatus, whereas identification of the mitochondrial NOS remains controversial [41].…”

“…In skeletal muscle, three NOS are expressed: 1) neuronal NOS (NOS1 or nNOS); 2) inducible NOS (NOS2 or iNOS); 3) endothelial NOS (NOS3 or eNOS). In skeletal muscle, NOS1 and NOS3 are constitutively expressed while NOS2 is mainly found under inflammatory condition [41]. NOS1 is typically present in the sarcolemma linked to the dystrophin complex, whereas NOS3 seems localized in the mitochondria [27,42].…”

“…In physiological conditions, RONS are signaling molecules, involved in essential processes such as insulin action, immune response, apoptosis, autophagy, mitochondria biogenesis and differentiation [8,29,41]. On the other hand, continuous and high concentration of RONS induces oxidative and irreversible damage to proteins, lipids, RNA and DNA.…”

Mitochondrial Quality Control as a Therapeutic Target

“…The rationale was to improve the low NO production rates observed in some mitochondrial diseases and not necessarily to directly increase mitochondrial biogenesis. Some encouraging results were reported using arginine and citrulline to treat relative NO deficiency in MELAS patients (Koga et al, 2005;El-Hattab et al, 2012a;Tengan et al, 2012), although mitochondrial proliferation in an effort to compensate for the disease has been proposed as an underlying cause of impaired NO synthesis by these patients in the first place (Tengan et al, 2012).…”

Nuclear Recruitment of Neuronal Nitric-oxide Synthase by α-Syntrophin Is Crucial for the Induction of Mitochondrial Biogenesis

“…Upon conditions that cause cell energetic stress (i.e., physical exercise, cold, fasting), PGC-1␣ is induced and impinges the co-activation of transcription factors regulating the expression of mitochondrial proteins including those controlling replication and transcription of mtDNA as well as oxidative phosphorylation genes (21). Notably, NO can either stimulate PGC-1␣ phosphoactivation by AMPK or increase its expression via CREB-dependent transcription (19,22,23). The modulation of mitochondrial respiratory chain is another way by which NO impacts on mitochondrial function.…”