Sucrose nonfermenting AMPK-related kinase (SNARK) mediates contraction-stimulated glucose transport in mouse skeletal muscle

Abstract

The signaling mechanisms that mediate the important effects of contraction to increase glucose transport in skeletal muscle are not well understood, but are known to occur through an insulinindependent mechanism. Muscle-specific knockout of LKB1, an upstream kinase for AMPK and AMPK-related protein kinases, significantly inhibited contraction-stimulated glucose transport. This finding, in conjunction with previous studies of ablated AMPKα2 activity showing no effect on contraction-stimulated glucose transport, suggests that one or more AMPK-related protein kinases are important for this process. Muscle contraction increased sucrose nonfermenting AMPK-related kinase (SNARK) activity, an effect blunted in the muscle-specific LKB1 knockout mice. Expression of a mutant SNARK in mouse tibialis anterior muscle impaired contraction-stimulated, but not insulin-stimulated, glucose transport. Whole-body SNARK heterozygotic knockout mice also had impaired contraction-stimulated glucose transport in skeletal muscle, and knockdown of SNARK in C2C12 muscle cells impaired sorbitol-stimulated glucose transport. SNARK is activated by muscle contraction and is a unique mediator of contraction-stimulated glucose transport in skeletal muscle.LKB1 | Akt Substrate of 160 kDa | TBC1D1 | exercise

The regulation and function of the NUAK family

“…High expression of SNARK protein was also found in HL1 cardiomyocytes (X Sun & J Zhou, 2013, unpublished observations), as well as in the skeletal muscle and heart tissues of mice (Lefebvre & Rosen 2005). Interestingly, the more oxidative muscles (gastrocnemius and soleus), as well as the heart, appeared to express two forms of SNARK (Koh et al 2010). A recent study reported that SNARK expression is increased in skeletal muscle of human subjects with obesity as well as in response to with metabolic stressors, but not in type 2 DM (Rune et al 2009).…”

Effect of exercise intensity and AICAR on isoform-specific expressions of murine skeletal muscle PGC-1α mRNA: a role of β2-adrenergic receptor activation

“…Activation of sucrose nonfermenting AMPK-related kinase (SNARK) by exercise is a candidate for other mechanisms. Muscle contraction-and exercise-induced activation of SNARK, one of the AMPK-related kinases, was observed in mouse skeletal muscle, and muscle contraction-induced phosphorylation of AS160 or TBC1D1, which might be necessary for increase in glucose transport in skeletal muscle, was mediated by SNARK (19). AICAR treatment also could phosphorylate AS160 or TBC1D1 (37).…”

SNF1/AMP-Activated Protein Kinases: Genes, Expression and Biological Role

“…It has been shown that expression of a mutant SNARK in mouse tibialis anterior muscle impaired contraction-stimulated, but not insulin-stimulated, glucose transport. The impaired contraction-stimulated glucose transport was also observed in skeletal muscle of whole-body SNARK heterozygotic knockout mice [30]. Thus, SNARK, the fourth member of the AMP-activated protein kinase catalytic subunit family, is activated by muscle contraction and is a unique mediator of contraction-stimulated glucose transport in skeletal muscle.…”

“…Recently, Koh et al [30] showed that muscle contraction also increases protein kinase SNARK activity and that this effect blunted in the muscle-specific LKB1 knockout mice. It is known that the signaling mechanisms that mediate the important effects of contraction, to increase glucose transport in skeletal muscle, occur through an insulin-independent mechanism.…”