Type 2 diabetes-related sarcopenia: role of nitric oxide

Abstract

Sarcopenia, characterized by progressive and generalized loss of skeletal muscle (SkM) mass, strength, and physical performance, is a prevalent complication in type 2 diabetes (T2D). Nitric oxide (NO), a multifunctional gasotransmitter involved in whole-body glucose and insulin homeostasis, plays key roles in normal SkM physiology and function. Here, we highlight the role of NO in SkM mass maintenance and its potential contribution to the development of T2D-related sarcopenia. Physiologic NO level, primarily produced by sarcolemmal neuronal nitric oxide synthase (nNOSμ isoform), is involved in protein synthesis in muscle fibers and maintenance of SkM mass. The observed effect of nNOSμ on SkM mass is muscle-type specific and sex-dependent. Impaired NO homeostasis [due to a diminished nNOSμ-NO availability and excessive NO production through inducible NOS (iNOS) in response to atrophic stimuli, e.g., inflammatory cytokines] in SkM occurred during the development and progression of T2D, may cause sarcopenia. Theoretically, restoration of NO through nNOS overexpression, supplying NOS substrates (e.g., L-arginine and L-citrulline), phosphodiesterase (PDE) inhibition, and supplementation with NO donors (e.g., inorganic nitrate) may be potential therapeutic approaches to preserve SkM mass and prevents sarcopenia in T2D.

Keywords: L-arginine; Nitrate; Nitric oxide; Sarcopenia; Skeletal muscle mass; Type 2 diabetes.

Fig. 1

Main anabolic and catabolic pathways coordinating protein balance and skeletal muscle (SkM) mass regulation and the role of nitric oxide (NO). Signaling pathways are initiated through various hormones (e.g., insulin, IGF-I, EP, NEP), nutrients (amino acids), energy state and physical activity (e.g., AMP-to-ATP ratio, AMPK), environmental stress (e.g., cytokines, LPS). Key signaling molecules that integrate these stimuli into protein synthesis and degradation are PI3K/Akt, mTORC1, GSK-3β and FoxO. α-Syn, α-syntrophin; AAs, amino acids; ActIIβ, activin type IIβ; AMP, adenosine monophosphate; AMPK; AMP-activated protein kinase; ATP, adenosine triphosphate; β₂-AR, β₂- adrenergic receptor; CaM, calmodulin; CaMK, CaM-dependent protein kinase; cGMP, cyclic guanosine monophosphate; CLC1, chloride voltage-gated channel 1; DGC, dystrophin-associated glycoprotein complex; EP, epinephrine; 4EBP1, 4E-binding protein 1; eNOS, endothelial nitric oxide synthase; eIF3f, eukaryotic translation initiation factor 3 subunit F; FoxO; forkhead box O; GTP, guanosine triphosphate; iNOS; inducible nitric oxide synthase; IGF-1, insulin-like growth factor 1; GSK-3β, glycogen synthase kinase-3β; IKKβ, inhibitory kappa B kinase β; IRS, insulin receptor substrate; JNK, c-Jun N-terminal kinase; LPS, lipopolysaccharides; MAFbx, muscle atrophy F-box; mTOR, mammalian target of rapamycin; MOV, mechanical overload; MuRF1, muscle ring finger 1; MA ion channels, mechanically-activated ion channels; NEP, norepinephrine; NFAT, nuclear factor of activated T-cells; NR, nitrate reductase; NFκB, nuclear factor kappa B; nNOS, neuronal nitric oxide synthase; NO₃, nitrate; ONOO⁻, peroxynitrite; PI3K, phosphoinositide 3-kinase; PKG, protein kinase G; PLD, phospholipase D; sGC, soluble guanylate cyclase; RNS, reactive nitrogen species; ROS, reactive oxygen species; RyR1; ryanodine receptor 1 Ca²⁺ release channel; SIRT1, silent mating type information regulation 2 homolog 1; SR, sarcoplasmic reticulum; SMAD, small mothers against decapentaplegic-related protein; TNF-α, tumor necrosis factor-α; TNFR, tumor necrosis factor-α receptor; TRPV1, transient receptor potential cation channel, subfamily V, member 1; TSC2, tuberous sclerosis complex 2; XOR, xanthine oxidoreductase