Abstract
Skeletal muscles respond to environmental and physiological changes by varying their size, fiber type, and metabolic properties. P38 mitogen-activated protein kinase (MAPK) is one of several signaling pathways that drive the metabolic adaptation of skeletal muscle to exercise. p38 MAPK also participates in the development of pathological traits resulting from excessive caloric intake and obesity that cause metabolic syndrome and type 2 diabetes (T2D). Whereas p38 MAPK increases insulin-independent glucose uptake and oxidative metabolism in muscles during exercise, it contrastingly mediates insulin resistance and glucose intolerance during metabolic syndrome development. This article provides an overview of the apparent contradicting roles of p38 MAPK in the adaptation of skeletal muscles to exercise and to pathological conditions leading to glucose intolerance and T2D. Here, we focus on the involvement of p38 MAPK in glucose metabolism of skeletal muscle, and discuss the possibility of targeting this pathway to prevent the development of T2D.
Highlights
Several inducible transcription factors rapidly and robustly increase PGC1α gene expression; cAMP Response Element-Binding Protein (CREB) and Activating Transcription Factor 2 (ATF2) [56], that bind to cAMP-response elements (CRE), and Mef2C and D [57], that bind to the YTA(A/T)4TAR sequence found within regulatory sequences of the Pgc-1α gene
Despite the substantial progress in understanding p38 mitogen-activated protein kinase (MAPK) involvement in the regulation of glucose metabolism in skeletal muscle, there remain open questions concerning the identities and involvement of p38 MAPK isoforms in different physiologic states and their modes of affecting their metabolic targets
Insulin resistance and sarcopenia develop mainly in obese and old immobile individuals due to dysregulated energy metabolism of skeletal muscles, and p38 MAPK is involved in the development of these maladies
Summary
Skeletal muscle comprises about 40% of the total body mass and accounts for around 30% of resting metabolic rate [1]. Due to its role in locomotion, this tissue is a major energy consumer, especially during exercise. It is the primary site of glucose disposal and the major glycogen storage organ and is, absolutely critical for glycemic control and the metabolic homeostasis of the body [2]. Since ATP’s resting intramuscular stores are small, energy needs to tightly regulate the metabolic pathways that generate ATP to maintain ATP at constant levels. The primary carbohydrate energy source in skeletal muscle is glucose that is processed from internal glycogen stores (glycogenolysis) or is extracted from the blood
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