Skeletal muscle glucose uptake during exercise: A focus on reactive oxygen species and nitric oxide signaling

Abstract

SummaryLike insulin, muscle contraction (in vitro or in situ) and exercise increase glucose uptake into skeletal muscle. However, the contraction/exercise pathway of glucose uptake in skeletal muscle is an independent pathway to that of insulin. Indeed, skeletal muscle glucose uptake is normal during exercise in those who suffer from insulin resistance and diabetes. Thus, the pathway of contraction-mediated glucose uptake into skeletal muscle provides an attractive potential target for pharmaceutical treatment and prevention of such conditions, especially as skeletal muscle is the major site of impaired glucose disposal in insulin resistance. The mechanisms regulating skeletal muscle glucose uptake during contraction have not been fully elucidated. Potential regulators include Ca 21(via CaMK's and/or CaMKK), AMPK, ROS, and NO signaling, with some redundancy likely to be evident within the system. In this review, we attempt to briefly synthesize current evidence regarding the potential mechanisms involved in regulating skeletal muscle glucose uptake during contraction, focusing on ROS and NO signaling. While reading this review, it will become clear that this is an evolving field of research and that much more work is required to elucidate the mechanism(s) regulating skeletal muscle glucose uptake during contraction.

The effect of metformin and exercise on serum lipids, nitric oxide synthase and liver nitric oxide levels in streptozotocin-nicotinamide induced diabetic rats

“…The mechanism (s) through which exercise stimulates GLUT4 translocation and glucose uptake appear to arise from local factors within skeletal muscle such as NO. There is building evidence that NO is important for the regulation of glucose uptake into skeletal muscle of rodents and humans during contraction/exercise independent of blood flow, and likely to be associated with signaling GLUT4 translocation (Merry and McConell, 2009). Exercise, from a metabolic perspective, may promote increased plasma arginine levels by increasing amino acid mobilization from skeletal muscle, thus normalizing cellular production of NO (Newsholme et al, 2010).…”

Purinergic receptors expressed in human skeletal muscle fibres

“…The mu isoform of nNOS (nNOSμ) is the primary form expressed in skeletal muscle and its activity, and the resulting NO-production, increases by 1.5-2-fold with contraction [43]. Interestingly, a reduced content of nNOSμ has been found in humans with impaired glucose homeostasis [40].…”

β-Conglycinin Peptides Improve Glucose Uptake through the AMPK Signaling Pathway in L6 Myotubes

“…AMPK activation is regulated by various biological factors, and NO is one of the activators for AMPK in skeletal muscle (Merry, et al, 2009). To clarify whether NO is involved in βCG peptide-induced glucose uptake activity, L-NMMA was introduced as an eNOS inhibitor (Figure 6).…”

“…Further supporting an AMPK activation role for βCG peptides, L-NMMA did not affect βCG peptideinduced glucose uptake activity (Figure 6), suggesting that NO was not involved in βCG peptide-induced glucose uptake activity in L6 myotubes. AMPK activation is regulated by various biological factors, including LKB1 (Merry, et al, 2009). LKB1 activates AMPK and contributes to signal transduction from adiponectin receptor 1 (AR1) (Kadowaki and Yamauchi, 2005;Zhou, et al, 2009).…”

“…The degree of AMPK activation depends on the intensity of exercise and is thought to be induced by changes in AMP/ATP and creatine/phosphocreatine ratios. Nitric oxide (NO) is also thought to regulate AMPK activation during exercise (Merry, et al, 2009). It has been reported that AMPK is activated by the anti-diabetic drugs metformin (Zhou, et al, 2001) and thiazolidinediones (Fryer, et al, 2002).…”