Role of nitric oxide and nitric oxide synthases in experimental models of denervation and reinnervation

Abstract

Nitric oxide (NO) is a short-living free molecule synthesized by three different isoforms of nitric oxide synthases (NOS)-neuronal NOS, endothelial NOS, and inducible NOS-associated with neuromuscular transmission, muscle contractility, mitochondrial respiration, and carbohydrate metabolism in skeletal muscle. Neuronal NOS is constitutively expressed at the muscle fiber sarcolemma linked to the dystrophin-glycoprotein complex and concentrated at the neuromuscular endplate. There is increasing evidence that altered expression of neuronal NOS plays a role in muscle fiber damage in neuromuscular diseases such as dystrophinopathies and denervating disorders. Although there have been some previous conflicting results on the neuronal NOS expression pattern in denervated muscle fibers, it is now well established that denervation is associated with a down-regulation and disappearance of sarcolemmal neuronal NOS at synaptic/extrasynaptic or both sites. As NO has been shown to induce collapse and growth arrest on neuronal growth cones, down-regulation of sarcolemmal neuronal NOS may contribute to axonal regeneration and attraction to muscle fibers aiming at the formation of new motor endplates providing reinnervation and reconstitution of NOS expression. As NO serves as a retrograde messenger, it may trigger structural downstream events responsible for neuromuscular synaptogenesis and preventing polyneural innervation. Nevertheless, decreased NO production in denervation reduces the cytoprotective scavenger function of NO for superoxide anions promoting oxidative stress that is likely to be involved in muscle fiber damage and death. However, the multifaced role of NOS and NO under physiological and pathological conditions remains poorly understood on the basis of the current knowledge.

Nitric Oxide Sustains Long-Term Skeletal Muscle Regeneration by Regulating Fate of Satellite Cells Via Signaling Pathways Requiring Vangl2 and Cyclic GMP

“…This might lead to a re‐evaluation of the role of NO in early myogenesis, in which the role of this messenger has been poorly investigated to date. In addition, some of the actions through which NO acts to regulate adult muscle function are independent of cGMP but the precise effectors have not always been identified [33, 34, 62, 63]. Assessment of the involvement in these events of NO‐dependent Wnt‐signaling would lead to a better understanding of its contribution to skeletal muscle physiology.…”

Local isoform‐specific NOS inhibition: A promising approach to promote motor function recovery after nerve injury

“…A return to nNOS control values parallels functional recovery, beginning in the second week after injury. On the other hand, eNOS and iNOS are up‐regulated in activated satellite cells or myotubes while muscle re‐innervation is happening (Tews, 2001; Chen et al, 2008). This supports NO involvement in re‐establishing neuromuscular junctions after muscle denervation.…”

Differential gene expression profiling of short and long term denervated muscle

“…Two recently identified ubiquitin ligases, atrogin‐1 and MuRF1, are instrumental in the development of reversible muscle atrophy after traumatic insults such as short‐term denervation, unweighting, and a variety of metabolic insults such as uremia, sepsis, diabetes, cancer cachexia, and fasting, demonstrating recruitment of common pathways across models of atrophy (20–23). Nonproteasomal proteolytic enzymes including the calpains (24, 25) and cathepsins (21) together with several other signaling networks such as TGFβ/MAPK cascade (26), Jak‐Stat (21), oxidative stress responses (27, 28), and NF‐κB activation have also been implicated in the induction of muscle atrophy associated with various experimental models and disease states. Programmed cell death also contributes to the loss of muscle mass with pro‐apoptotic genes such as bax and caspases 1 and 8 up‐regulated in the short‐term denervated muscle (29–31).…”