The role of group I p21-activated kinases in contraction-stimulated skeletal muscle glucose transport

Abstract

20Aim: Muscle contraction stimulates skeletal muscle glucose transport. Since it occurs inde-21 pendently of insulin, it is an important alternative pathway to increase glucose uptake in insu-22 lin-resistant states, but the intracellular signalling mechanisms are not fully understood. Muscle 23 contraction activates group I p21-activated kinases (PAKs) in mouse and human skeletal mus-24 cle. PAK1 and PAK2 are downstream targets of Rac1, which is a key regulator of contraction-25 stimulated glucose transport. Thus, PAK1 and PAK2 could be downstream effectors of Rac1 26 in contraction-stimulated glucose transport. The current study aimed to test the hypothesis that 27 PAK1 and/or PAK2 regulate contraction-induced glucose transport. Methods: Glucose 28 transport was measured in isolated soleus and extensor digitorum longus (EDL) mouse skeletal 29 muscle incubated either in the presence or absence of a pharmacological inhibitor (IPA-3) of 30 group I PAKs or originating from whole-body PAK1 knockout (KO), muscle-specific PAK2 31 (m)KO or double whole-body PAK1 and muscle-specific PAK2 knockout mice. Results: IPA-32 3 attenuated (-22%) the increase in muscle glucose transport in response to electrically-stimu-33 lated contraction. PAK1 was dispensable for contraction-stimulated glucose uptake in both so-34 leus and EDL muscle. Lack of PAK2, either alone (-13%) or in combination with PAK1 (-35 14%), reduced contraction-stimulated glucose transport compared to control littermates in 36 EDL, but not soleus muscle. Conclusion: Contraction-stimulated glucose transport in isolated 37 glycolytic mouse EDL muscle is partly dependent on PAK2, but not PAK1. 38 Keywords 39 Contraction; Glucose uptake, Metabolism; p21-activated kinase; Skeletal muscle.40 41Muscle contraction increases skeletal muscle glucose uptake independently of insulin 1-3 . Ac-42 cordingly, muscle contraction increases glucose uptake in both insulin-sensitive and insulin-43 resistant skeletal muscle 4-6 . Additionally, insulin sensitivity is improved after cessation of 44 muscle contraction 7-10 , making muscle contraction during acute exercise a non-pharmacolog-45 ical treatment for insulin resistance 11 . However, while muscle contraction is known to promote 46 the translocation of the glucose transporter (GLUT)-4 to the plasma membrane, which facili-47 tates glucose entry into the muscle, the intracellular signalling regulating this process is not 48 completely understood. 49Upon muscle contraction, multiple intracellular signalling pathways are activated that promote 50 GLUT4 translocation and a subsequent increase in muscle glucose transport. Redundant Ca +2 -51 dependent signalling, metabolic stress signalling, and mechanical stress signalling are proposed 52 to regulate distinct steps important for glucose transport in response to muscle contraction 12 . 53The group I p21-activated kinase (PAK)-1 and PAK2 are activated in response to electrical 54 pulse stimulation in C2C12 myotubes 13,14 and muscle contraction/acute exercise in mouse and 55 human sk...