Intensity-dependent activation of intracellular signalling pathways in skeletal muscle: role of fibre type recruitment during exercise

Physical activity elicits physiological responses in skeletal muscle that result in a number of health benefits, in particular in diseases associated with peripheral metabolic dysfunction such as diabetes, heart failure or chronic obstructive pulmonary disease. These diseases have been associated with altered skeletal muscle metabolism and, in some cases, diminished ATP production, decreased mitochondrial content, and a higher proportion of type II fast glycolytic fibre. Exercise training is one intervention that can increase the percentage of oxidative fibres (type I, slow) and have a beneficial impact on these disease states. Several studies have compared the effects of continuous vs. interval training, and have determined that interval training may be the most effective exercise strategy to promote mitochondrial biogenesis and enhance muscle oxidative capacity. The importance of exercise in regulating skeletal muscle metabolism is well appreciated; however, the molecular mechanisms that underlie the beneficial adaptations to exercise remain to be fully understood. Peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) is a key factor involved in the regulation of multiple myocellular signalling pathways such as those implicated in mitochondrial biogenesis and fibre type expression (Russell et al. 2003). Although muscle contraction is known to strongly modulate PGC-1α expression in human skeletal muscle, little is known about the underlying intracellular mechanisms involved. The differential activation across varying training protocols may shed light onto the regulation of signalling pathways upstream of PGC-1α. This Journal Club article discusses the paper of Egan et al. (2010) published recently in The Journal of Physiology and suggests that differences in fibre type recruitment may explain some of the results. Egan et al. compared the effects two isocaloric bouts of exercise performed at either low or high intensity on skeletal muscle signalling. Eight sedentary males performed two trials on a stationary ergocycle: the low- and high-intensity exercise consisted of continuous cycling at 40% or 80% of peak oxygen consumption (), respectively, until the caloric expenditure reached 400 kcal (1674 kJ). Muscle biopsies from the vastus lateralis were taken at rest and at +0, +3 and +19 h after both exercise bouts. The dietary intake during each experimental trial was controlled. PGC-1α mRNA increased 3 h after both exercise bouts; they observed a 3.8-fold increase after low-intensity exercise whereas it increased 10.2-fold after high-intensity training, supporting an intensity-dependent regulation of PGC-1α expression. The authors also explored the signalling pathways upstream of PGC-1α. Protein quantification by immunoblotting revealed a differential activation of multiple signalling pathways involved directly and indirectly in the regulation of PGC-1α transcription. The higher PGC-1α mRNA abundance after high-intensity exercise also coincided with a greater phosphorylation of activating transcription factor-2 (ATF-2) and of class IIa histone deacetylase (HDAC) proteins also suggesting that ATF-2 and HDAC proteins were involved in an intensity-dependent manner. The authors concluded that the intensity during a single bout of exercise regulates PGC-1α mRNA abundance by activating selected upstream signalling pathways in human skeletal muscle with an intensity-dependent response.