Mechanisms regulating metabolic and mitogenic events in skeletal muscle : implications for insulin resistance and exercise

Reduced glucose transport in skeletal muscle is a hallmark feature of Type II diabetes. Numerous mechanisms acutely or chronically regulate skeletal muscle glucose transport. The role of GLUT4, mitogen-activated protein kinases (MAPK), and peroxisome proliferator-activated receptor [gamma] (PPAR[gamma]) were examined in skeletal muscle.

The role of GLUT4 was first considered. Insulin increased 2-deoxyglucose uptake 2.8-and 2.1-fold in Wild-type versus GLUT4-deficient (GLUT4-null) soleus muscle. GLUT4 ablation did not increase GLUT3 or GLUT5 protein in soleus muscle. Insulin-stimulated cell surface GLUT1 content was similar in Wild-type and GLUT4-null soleus muscle.

Hypoxia stimulated glucose uptake 2- to 2.5- fold in Wild-type EDL or soleus muscle, but was without effect in GLUT4-null muscle. Introduction of the MLC-GLUT4 transgene into GLUT4-null mice restored hypoxia-stimulated glucose uptake in EDL muscle.

Exercise, but not insulin, significantly increased glucose uptake in EDL muscle from fed GLUT4-null mice. However, the exercise effect was reduced compared to Wild-type mice. Exercise led to a similar degree of muscle glycogen depletion in Wild-type and GLUT-null mice. Glycogen was restored in Wild-type mice by 5 h after exercise, whereas restoration of glycogen in GLUT4-null mice was observed 24 h post-exercise.

In muscle from healthy human subjects, insulin and hypoxia similarly stimulated glucose transport and GLUT4 translocation. Glucose transport and GLUT4 translocation were markedly reduced in diabetic skeletal muscle in response to either insulin or hypoxia. A greater defect was observed in GLUT4 translocation.

Mitogenic events are under control of the MAPK-signaling pathways. In vitro muscle contraction increased ERK1/2 and p38 MAPK phosphorylation and p90Rsk, MAPKAP-K2, and MSK1 activity in rat epitrochlearis muscle. The MEK1 inhibitor, PD98059, completely abolished contraction-mediated ERK1/2, p90Rsk, and MSK1 activity. The p38 MAPK inhibitor, SB203580, prevented p38 MAPK, MAPKAP-K2, and MSK1 activation.

Thiazolidinediones (TZD: PPAR[gamma] agonists) are a new class of anti-diabetic drugs. Oral TZD-treatment partially restored in vivo glucose uptake and normalized in vitro glucose uptake in ZDF rat and ob/ob mouse skeletal muscle, respectively. However, in vitro TZD-exposure (5-9h) did not improve insulin-stimulated glucose uptake in soleus muscle from ob/ob mice.

In conclusion, GLUT4 is a major regulatory factory for both insulin- and exercise stimulated glucose transport. However, GLUT4-independent mechanisms exist in skeletal muscle. Furthermore, defects in GLUT4 translocation may contribute to Type II diabetes. Exercise-induced improvements in skeletal muscle insulin action likely involve direct activation of MAPK-signaling pathways in response to muscle contraction, whereas improved insulin action in muscle following TZD treatment is secondary to PPAR[gamma] activation in other tissues.

List of scientific papers

I. Ryder JW, Kawano Y, Chibalin AV, Rincon J, Tsao TS, Stenbit AE, Combatsiaris T, Yang J, Holman GD, Charron MJ, Zierath JR (1999). In vitro analysis of the glucose-transport system in GLUT4-null skeletal muscle. Biochem J. 342 ( Pt 2): 321-328.
https://pubmed.ncbi.nlm.nih.gov/99386662

II. Zierath JR, Tsao TS, Stenbit AE, Ryder JW, Galuska D, Charron MJ (1998). Restoration of hypoxia-stimulated glucose uptake in GLUT4-deficient muscles by muscle-specific GLUT4 transgenic complementation. J Biol Chem. 273(33): 20910-20915.
https://pubmed.ncbi.nlm.nih.gov/98361959

III. Ryder JW, Kawano Y, Galuska D, Fahlman R, Wallberg-Henriksson H, Charron MJ, Zierath JR (1999). Postexercise glucose uptake and glycogen synthesis in skeletal muscle from GLUT4-deficient mice. FASEB J. 13(15): 2246-2256.
https://pubmed.ncbi.nlm.nih.gov/20062717

IV. Ryder JW, Yang J, Galuska D, Rincon J, Bjornholm M, Krook A, Lund S, Pedersen O, Wallberg-Henriksson H, Zierath JR, Holman GD (2000). Use of a novel impermeable biotinylated photolabeling reagent to assess insulin- and hypoxia-stimulated cell surface GLUT4 content in skeletal muscle from type 2 diabetic patients. Diabetes. 49(4): 647-654.
https://pubmed.ncbi.nlm.nih.gov/20327019

V. Ryder JW, Fahlman R, Wallberg-Henriksson H, Alessi DR, Krook A, Zierath JR (2000). Effect of contraction on mitogen-activated protein kinase signal transduction in skeletal muscle. Involvement Of the mitogen- and stress-activated protein kinase 1. J Biol Chem. 275(2): 1457-1462.
https://pubmed.ncbi.nlm.nih.gov/20092926

VI. Zierath JR, Ryder JW, Doebber T, Woods J, Wu M, Ventre J, Li Z, McCrary C, Berger J, Zhang B, Moller DE (1998). Role of skeletal muscle in thiazolidinedione insulin sensitizer (PPARgamma agonist) action. Endocrinology. 139(12): 5034-5041.
https://pubmed.ncbi.nlm.nih.gov/99049282