Abstract
Skeletal muscle glucose uptake and glucose metabolism are impaired in insulin resistance. Mechanical overload stimulates glucose uptake into insulin-resistant muscle; yet the mechanisms underlying this beneficial effect remain poorly understood. This study examined whether a differential partitioning of glucose metabolism is part of the mechanosensitive mechanism underlying overload-stimulated glucose uptake in insulin-resistant muscle. Mice were fed a high-fat diet to induce insulin resistance. Plantaris muscle overload was induced by unilateral synergist ablation. After 5 days, muscles were excised for the following measurements: (1) [3H]-2-deoxyglucose uptake; (2) glycogen; 3) [5-3H]-glucose flux through glycolysis; (4) lactate secretion; (5) metabolites; and (6) immunoblots. Overload increased glucose uptake ~80% in both insulin-sensitive and insulin-resistant muscles. Overload increased glycogen content ~20% and this was enhanced to ~40% in the insulin-resistant muscle. Overload did not alter glycolytic flux, but did increase muscle lactate secretion 40–50%. In both insulin-sensitive and insulin-resistant muscles, overload increased 6-phosphogluconate levels ~150% and decreased NADP:NADPH ~60%, indicating pentose phosphate pathway activation. Overload increased protein O-GlcNAcylation ~45% and this was enhanced to ~55% in the insulin-resistant muscle, indicating hexosamine pathway activation. In conclusion, insulin resistance does not impair mechanical overload-stimulated glucose uptake but does alter the metabolic fate of glucose in muscle.
Highlights
Exercise training is one of the most well-established therapeutic strategies for the treatment of progressive metabolic diseases such as type 2 diabetes [1,2,3,4,5,6,7,8]
While previous work has demonstrated that resistance exercise training and chronic mechanical muscle loading stimulate glucose uptake into both insulin-sensitive and insulin-resistant skeletal muscle [9,10], the cellular or metabolic adaptations that underlie these beneficial effects are still largely unknown
Glucose uptake into skeletal muscle is regulated by the presence of cell surface glucose transporters as well as its metabolic fate, including: (1) storage as glycogen; (2) flux via glycolysis; (3) the pentose phosphate pathway; and (4) the hexosamine pathway
Summary
Exercise training is one of the most well-established therapeutic strategies for the treatment of progressive metabolic diseases such as type 2 diabetes [1,2,3,4,5,6,7,8]. While previous work has demonstrated that resistance exercise training and chronic mechanical muscle loading (overload) stimulate glucose uptake into both insulin-sensitive and insulin-resistant skeletal muscle [9,10], the cellular or metabolic adaptations that underlie these beneficial effects are still largely unknown. Studies have linked excessive muscle glycogen accumulation and increased glucose flux through the hexosamine pathway with the development of muscle insulin resistance [11,12,13,14,15], highlighting the importance of glucose metabolism in regulating future increases in muscle glucose uptake. Changes in glucose metabolism such as increased glycolytic flux and activation of the pentose phosphate pathway have been linked with enhanced cellular growth in a variety of cell types [16,17,18,19]. Whether overload directs glucose flux into other metabolic pathways, and whether this partitioning of glucose is affected by insulin resistance, has not yet been examined
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