Exercise effects on the mitogen-activated protein (MAP) kinase cascade in skeletal muscle

Exercise-induced adaptations in skeletal muscle are regulated by numerous signaling mechanisms. However, little is known about the molecular signaling mechanisms linking muscle contraction or other exercise-associated stimuli to intracellular responses in skeletal muscle. The major focus of this thesis has been to elucidate the role of the MAP kinase cascade in response to acute exercise. The involvement of MAP kinase cascades in response to isolated isometric contractions in skeletal muscle was assessed. ERK1/2 and p38 MAP kinase phosphorylation was increased 1.6- and 2.3-fold, respectively by contractions, with no change in ERK1/2 and p38 MAP kinase protein expression. ERK1/2 displayed a fiber-type specific pattern of protein expression, with the greatest amount in slow-twitch (soleus) muscle. Acute exercise in human skeletal muscle has a divergent effect on parallel MAP kinase pathways. Phosphorylation of MEK1/2, ERK1/2, SEK1 and p38 MAP kinase was rapidly increased in exercised muscle. Exercise elicited an intensity-dependent increase in MEK1/2 and ERK1/2 phosphorylation, with systematic increases in phosphorylation noted between basal, low, and high intensity exercise. Phosphorylation of p38 MAP kinase was also elevated in the non-exercised muscle, suggesting systemic factors might play a role in phosphorylating this kinase. The magnitude of exercise-induced phosphorylation of ERK1/2 was more profound than for the other kinases. After freeze-drying and further purification of skeletal muscle, exercise-induced ERK1/2 phosphorylation was noted to occur mainly directly in the skeletal muscle fibers. In contrast to effects on MAP kinase proteins, exercise did not increase Akt kinase activity or tyrosine phosphorylation of IR, IRS-1 or PYK2. Exercise increased activity of downstream targets of ERK1/2 and p38 MAP kinase including MSK1, MSK2, p90rsk, and MAPKAPK2. Activation of these substrates follows ERK1/2 phosphorylation, suggesting MAP kinase signaling cascades mediate exercise-induced changes in transcription and gene expression. In conclusion, acute exercise elicits signal transduction via MAP kinase cascades, specifically in direct response to contraction in skeletal muscle. Further, MAP kinase signaling pathways appear to be potential physiologic mechanisms involved in exercise-induced regulation of gene expression in skeletal muscle.

List of scientific papers

I. Wretman C, Widegren U, Lionikas A, Westerblad H, Henriksson J (2000). Differential activation of mitogen-activated protein kinase signalling pathways by isometric contractions in isolated slow- and fast-twitch rat skeletal muscle. Acta Physiol Scand. 170(1):45-9.
https://pubmed.ncbi.nlm.nih.gov/10971222

II. Widegren U, Jiang XJ, Krook A, Chibalin AV, Bjornholm M, Tally M, Roth RA, Henriksson J, Wallberg-henriksson H, Zierath JR (1998). Divergent effects of exercise on metabolic and mitogenic signaling pathways in human skeletal muscle. FASEB J. 12(13):1379-89.
https://pubmed.ncbi.nlm.nih.gov/9761781

III. Widegren U, Wretman C, Lionikas A, Hedin G, Henriksson J (2000). Influence of exercise intensity on the ERK/MAP kinase signalling in human skeletal muscle. Plugers Archiv. 441(2-3):317-22.
https://pubmed.ncbi.nlm.nih.gov/11211119

IV. Krook A, Widegren U, Jiang XJ, Henriksson J, Wallberg-Henriksson H, Alessi D, Zierath JR (2000). Effects of exercise on mitogen- and stress-activated kinase signal transduction in human skeletal muscle. Am J Physiol Regul Integr Comp Physiol. 279(5):R1716-21.
https://pubmed.ncbi.nlm.nih.gov/11049854