Exercise-induced signal transduction and gene regulation in skeletal muscle

Abstract

Skeletal muscle adapts to various forms of exercise depending on the force, speed and duration characteristics of the contraction pattern. The stresses and signals associated with each contraction pattern are likely to specifically activate a network of signal transduction pathways that integrate this information. These pathways include the calcineurin, Calcium/calmodulin-dependent protein kinase (CaMK), mitogen-activated protein kinase (MAPK), protein kinase C (PKC), nuclear factor kappa B (NF-κB), AMP-dependent protein kinase (AMPK), insulin signalling and developmental pathways. Activated signal transduction pathways activate or increase the expression of transcription factors via various mechanisms. Skeletal muscle genes are usually regulated by combinatorial control exerted by several transcription factors and possibly other mechanisms. In addition, adaptations such as an increase in mitochondrial biogenesis or the activation of satellite cell proliferation involve distinct regulatory mechanisms.

Keywords: Adaptation; calcineurin myosin heavy chain; mitochondrial biogenesis; satellite cells.

Figure 1.

An overview of exercise-induced adaptation signalling and gene regulation in skeletal muscle. Exercise activates signal transduction pathways via (1) growth factors and hormones binding to membrane and nuclear receptors, (2) Ca²⁺ concentration changes, mechanical stretch, energy status, hypoxia and (3) cell damage/injury. Numerous, sometimes cross-talking signal transduction proteins signal mainly but not exclusively by covalent phosphorylation (4). In a final step, a nuclear localisation signal (yellow) is activated and translocated into the nucleus (Cyert, 2001). Inside the nucleus (6), the signalling protein either acts as a transcription factor itself or it activates transcription factors that will bind regulatory DNA sequences. Skeletal muscle genes are controlled by several regulatory elements and a cross-talk with developmental programmes is likely. Exercise-induced effects include (7) expression of growth factors, (8) contractile proteins, enzymes and other functional proteins, (9) satellite cell proliferation and donation of nuclei to skeletal muscle fibres, (10) mitochondrial biogenesis, and (11) apoptosis.

Figure 2.

Relative amounts of myosin heavy chain (MHC) isoform IIx (a) and IIb (b) mRNA (mean ± SEM, n=4) in cultured rat myocytes (muscle cells) measured with Northern blotting (Higginson et al., 2002). ▲ Control (no pharmacological treatment). ● Cyclosporin A (calcineurin pathway inhibitor) treated. ■ U0126 (ERK1/2 pathway inhibitor) treated. Blockade of the calcineurin pathway resulted in significantly higher levels of MHC IIx while blockade of the ERK1/2 pathway resulted in significantly higher levels of MHC IIx and MHC IIb. These results suggest that the calcineurin pathway suppresses the MHC IIx isoform when activated by exercise. The ERK1/2 pathway suppresses the MHC IIx and MHC IIb isoforms when activated by exercise.