Abstract
AimMuscle contraction stimulates skeletal muscle glucose transport. Since it occurs independently of insulin, it is an important alternative pathway to increase glucose transport in insulin‐resistant states, but the intracellular signaling mechanisms are not fully understood. Muscle contraction activates group I p21‐activated kinases (PAKs) in mouse and human skeletal muscle. PAK1 and PAK2 are downstream targets of Rac1, which is a key regulator of contraction‐stimulated glucose transport. Thus, PAK1 and PAK2 could be downstream effectors of Rac1 in contraction‐stimulated glucose transport. The current study aimed to test the hypothesis that PAK1 and/or PAK2 regulate contraction‐induced glucose transport.MethodsGlucose transport was measured in isolated soleus and extensor digitorum longus (EDL) mouse skeletal muscle incubated either in the presence or absence of a pharmacological inhibitor (IPA‐3) of group I PAKs or originating from whole‐body PAK1 knockout, muscle‐specific PAK2 knockout or double whole‐body PAK1 and muscle‐specific PAK2 knockout mice.ResultsIPA‐3 attenuated (−22%) the increase in glucose transport in response to electrically stimulated contractions in soleus and EDL muscle. PAK1 was dispensable for contraction‐stimulated glucose transport in both soleus and EDL muscle. Lack of PAK2, either alone (−13%) or in combination with PAK1 (−14%), partly reduced contraction‐stimulated glucose transport compared to control littermates in EDL, but not soleus muscle.ConclusionContraction‐stimulated glucose transport in isolated glycolytic mouse EDL muscle is partly dependent on PAK2, but not PAK1.
Highlights
Muscle contraction increases skeletal muscle glucose uptake independently of insulin (Douen et al, 1990; Hansen, Gulve, & Holloszy, 1994; Lund, Holman, Schmitz, and Pedersen 1995; Ploug, Galbo, & Richter, 1984; Ploug, van Deurs, Ai, Cushman, & Ralston, 1998; Wallberg-Henriksson & Holloszy, 1985)
PACC1/2 S79/212 was normally phosphorylated in response to contractions in both muscles (Figure 3c+d). Another contraction-stimulated downstream target of AMPK, pTBC1D1 S231 was unaffected by lack of PAK1 and/or PAK2 in soleus muscle (Figure 3e), but was reduced (−39%) in extensor digitorum longus (EDL) muscle from 1/m2 dKO mice compared to PAK1 KO mice (Figure 3f)
The present study is, to our knowledge, the first to investigate the requirement of PAK1 and PAK2 in contraction-stimulated glucose transport in mouse skeletal muscle
Summary
Muscle contraction increases skeletal muscle glucose uptake independently of insulin (Douen et al, 1990; Hansen, Gulve, & Holloszy, 1994; Lund, Holman, Schmitz, and Pedersen 1995; Ploug, Galbo, & Richter, 1984; Ploug, van Deurs, Ai, Cushman, & Ralston, 1998; Wallberg-Henriksson & Holloszy, 1985). Multiple intracellular signaling pathways are activated that promote GLUT4 translocation and a subsequent increase in muscle glucose uptake. The group I p21-activated kinase (PAK)-1 and PAK2 are activated in response to electrical pulse stimulation in C2C12 myotubes (Hu et al, 2018; Yue et al, 2019) and muscle contraction/acute exercise in mouse and human skeletal muscle (Sylow et al, 2013). Rac plays a key role in mediating GLUT4 translocation and glucose uptake in response to muscle contraction and acute exercise in skeletal muscle (Sylow et al, 2013, 2016; Sylow, Møller, et al, 2017). Whereas PAK1 previously has been proposed to regulate insulin-stimulated GLUT4 translocation in skeletal muscle (Tunduguru et al, 2014; Wang, Oh, Clapp, Chernoff, & Thurmond, 2011), we recently identified PAK2, but not PAK1, as a partial requirement for insulin-stimulated glucose transport in mouse extensor digitorum longus (EDL) muscle (Moller et al, 2019). Our results identify PAK2, but not PAK1, as a partial requirement for contraction-stimulated glucose transport in mouse skeletal muscle
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