**4. Conclusions**

Despite the substantial progress in understanding p38 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 di fferent physiologic states and their modes of a ffecting their metabolic targets. Due to its massive energy consumption, skeletal muscle functionality is critical for maintaining whole-body glucose homeostasis. 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. Hence, depending on the physiological context, p38 MAPK activity may lead to harmful consequences of sarcopenia and insulin resistance in the immobile muscle or beneficial e ffects of increased glucose sensitivity and metabolism in the contracting muscle. This review summarized the involvement of p38 MAPK in glucose metabolism of skeletal muscle under the two extreme conditions of exercise (health) and obesity (disease), as schemed in Figure 1. In exercise training, muscle contraction utilizes an enormous amount of energy, supplied by the adaptation of muscles to glycolytic (resistance) or oxidative (endurance) glucose metabolism. Under these conditions, p38 MAPK facilitates glucose transport in an insulin-independent manner and improves insulin-dependent glucose transport by inducing transcription of genes encoding the glucose transporters, Glut1, and Glut4. P38 MAPK also increases oxidative metabolism by inducing the transcription and the activity of PGC1 α, the "master coactivator" of mitochondrial biogenesis and activity. Interestingly, in the contracting muscle, p38 MAPK is co-expressed with AMPK, the "energy sensor" of the cell. The activities of these two kinases synergistically increase glucose import in a pathway alternative to that of insulin. They also facilitate together mitochondrial oxidative metabolism to provide the necessary amount of energy for muscle contraction.

**Figure 1.** The involvement of p38 mitogen-activated protein kinase (MAPK) in glucose metabolism of skeletal muscle in health and disease. The upper half of the scheme describes the involvement of p38 MAPK in glucose metabolism of skeletal muscle in obesity: excessive intake of fatty acids and carbohydrates cause mitochondrial electron leak from the electron transport chain (ETC), accumulation of ROS, and mitochondrial dysfunction. Intramuscular fat metabolites (ceramide and DAG) reduce mitochondrial oxidative capacity and increase in the generation of mitochondrial reactive oxygen species (ROS) that induce p38 MAPK activity. Activated p38 MAPK inhibits IRS1 of insulin signaling through inhibitory phosphorylation. It also inhibits the transcription of *Pgc1*<sup>α</sup>*, Glut4* genes, and activates that of the *Glut1* gene. As a result, insulin-dependent glucose uptake is blocked, while insulin-independent glucose uptake is elevated. The lower half of the scheme describes the involvement of p38 MAPK in glucose metabolism of skeletal muscle in exercise: transient elevation in ROS induces the activity of p38 MAPK, which in turn stimulates the transcription of *Pgc1*α and *Glut4* genes. Besides, p38 phosphorylates PGC1α and augments its activity needed for mitochondrial integrity and function. P38 MAPK synergizes with AMPK in glucose uptake; the first increases the levels of Glut4 and the second drives the transport of vesicular Glut4 to the plasma membrane. Abbreviations: GSV, Glut4 storage vesicles; DAG, diacylglycerol; PI3-K, Phosphoinositide 3-kinase; PDK1, Phosphoinositide-dependent protein kinase-1; GSK3, Glycogen synthase kinase 3; GS, Glycogen synthase; IR, Insulin receptor; FA, Fatty acid.

In obesity, however, the activity of p38 MAPK contributes to the development of insulin resistance. The surplus in skeletal muscle calorie intake and the elevated levels of circulating fatty acids that penetrate muscle cells, increase intramuscular fat metabolites that reduce mitochondrial oxidative capacity and high electron leakage that generate ROS. ROS and lipid metabolites activate some kinases, including p38 MAPK, that impair the insulin-signaling pathway by phosphorylating serine/threonine residues of IRS1 and preventing tyrosine phosphorylation and activation of IRS1 by insulin. Consequently, insulin signaling is impaired and Glut4-mediated glucose uptake is prevented. The chronic activity of p38 MAPK also decreases the expression of PGC1 proteins and, consequently, diminishes glucose utilization by the mitochondria. Under these pathological conditions, p38 MAPK activates the *Glut1* gene expression and increases the basal diffusion of glucose independently of insulin signaling.

In sum, the p38 MAPK pathway is a double-edged sword that increases insulin-independent glucose uptake and mitochondrial oxidative phosphorylation in a healthy lifestyle while inhibiting, in unhealthy lifestyles, the same processes mediated by insulin signaling, leading to metabolic syndrome.

**Author Contributions:** E.B. and T.H. collected and analyzed the material, and wrote the paper. S.A. critically reviewed, commented and added changes to the paper. All authors have read and agreed to the published version of the manuscript.

**Funding:** This work was supported by a gran<sup>t</sup> from "Rappaport Family Institute for Research in the Medical Sciences".

**Acknowledgments:** We thank Michael Fry for critical reading of the manuscript.

**Conflicts of Interest:** The authors declare that they have no conflict of interest.
