Metabolic and mitogenic transduction cascades in skeletal muscle : implications for exercise effects on glucose metabolism and gene regulation

Level of physical activity is linked to improved glucose homeostasis. The molecular signaling mechanisms by which insulin and exercise/muscle contractions lead to increased glucose transport and metabolism and gene expression have not been completely elucidated. The overall aim of this thesis was to identify novel regulatory mechanisms governing exercise-sensitive signaling pathways to glucose metabolism and gene transcription in skeletal muscle. Components of the insulin (IRS 1 /P13-kinase) signaling cascade, as well as the mitogen-activated protein kinase (MAPK) and 5'AMP-activated protein kinase (AMPK) cascades were examined in skeletal muscle in response to exercise.

Exercise/muscle contraction leads to increased expression and function of several proteins in the insulin-signal transduction cascade in rat skeletal muscle. IRS I and IRS2 underwent differential regulation in skeletal muscle in response to acute or chronic exercise, indicating an isoform specific role in contracting muscle. However, early components involved in the insulin-signaling cascades were down-regulated in skeletal muscle from subjects engaged in habitual physical exercise program.

MAPK signaling cascades to downstream targets were activated in response to endurance and high intensity exercise in sedentary and well-trained subjects. Acute exercise-induced activation of MAPK occurs in parallel with AMPK signaling. Importantly, these signaling responses were greater in untrained subjects, even when exercise was performed at the same relative intensity. This suggests skeletal muscle from previously well-trained individuals requires a greater stimulus to activate signal transduction via these pathways.

Using an electrophoretic gel mobility shift assay, we reveal exercise and muscle contraction increased MEF2-DNA binding activity in nuclear extracts prepared from skeletal muscle. Using specific inhibitors of MAPK, we demonstrated exercise-induced MEF2-DNA binding requires ERK 1/2 and p38 MAPK- dependent pathways.

In conclusion, this dissertation work provides molecular mechanisms by which exercise enhances insulin action and gene expression in skeletal muscle. By identifying the molecular mechanisms controlling insulin sensitivity in response to exercise, new targets for pharmacological intervention have been revealed. Furthermore, a molecular basis is provided for physiological (exercise and diet) intervention strategies aimed to improve glucose homeostasis.

List of scientific papers

I. Chibalin AV, Yu M, Ryder JW, Song XM, Galuska D, Krook A, Wallberg-Henriksson H, Zierath JR (2000). Exercise-induced changes in expression and activity of proteins involved in insulin signal transduction in skeletal muscle: differential effects on insulin-receptor substrates 1 and 2. Proc Natl Acad Sci U S A. 97(1): 38-43.
https://pubmed.ncbi.nlm.nih.gov/10618367

II. Yu M, Blomstrand E, Chibalin AV, Wallberg-Henriksson H, Zierath JR, Krook A (2001). Exercise-associated differences in an array of proteins involved in signal transduction and glucose transport. J Appl Physiol. 90(1): 29-34.
https://pubmed.ncbi.nlm.nih.gov/11133890

III. Yu M, Blomstrand E, Chibalin AV, Krook A, Zierath JR (2001). Marathon running increases ERK1/2 and p38 MAP kinase signalling to downstream targets in human skeletal muscle. J Physiol. 536(Pt 1): 273-82.
https://pubmed.ncbi.nlm.nih.gov/11579175

IV. Yu M, Stepto NK, Chibalin AV, Fryer LG, Carling D, Krook A, Hawley JA, Zierath JR (2003). Metabolic and mitogenic signal transduction in human skeletal muscle after intense cycling exercise. J Physiol. 546(Pt 2): 327-35.
https://pubmed.ncbi.nlm.nih.gov/12527721