Responses of mouse skeletal muscle to endurance exercise. Functional, metabolic, and genomic adaptations

Abstract

Endurance exercise is commonly known to improve skeletal muscle performance with respect to fatigue resistance. The exact mechanisms, however, as to how skeletal muscle adapts to increased physical demand are still largely unknown, despite extensive research. These processes were originally studied in laboratory animals employing classic cross-innervation and chronic motor nerve stimulation experiments. In time, treadmill and running wheel exercise modalities became more popular due to their ability to study adaptation processes in a minimally invasive, in vivo, situation. In this respect, mouse skeletal muscle adaptations have been extensively investigated, mainly due to the increasing availability of transgenic animals. In order to extrapolate adaptations in transgenic mice to a human situation, however, it is essential to understand these processes in normal, wild-type mice. In the present thesis we have investigated the effects of six weeks endurance exercise on mouse skeletal muscle functioning, and associated metabolic and genomic changes. On of our first objective was to characterize the running pattern of voluntarily exercising mice. This clearly demonstrated an intermittent running pattern consisting of short bouts of high-speed running. This roughly compares to high-speed interval training in human, although there clearly are differences between these two. We further demonstrated that endurance exercise obviously improves fatigue resistance in both the slow-twitch soleus and the fast-twitch extensor digitorum longus (EDL) muscle, but that mouse skeletal muscle is remarkably robust in its myosin heavy chain (MyHC) phenotype. Studies in humans typically show changes in MyHC profile, the contractile proteins of skeletal muscle. Soleus musles further demonstrated improved capacity to relax during serial twitch contractions. This suggests improved Ca2+ recovery and was associated with changes in mRNA and protein expression of Ca2+ regulatory proteins. Further, exercised soleus muscle consumed more oxygen during these serial contraction, which was associated with changes in mRNA expression of genes related to oxygen/glucose metabolism. In EDL, no such changes were found, neither at the functional level, nor at the protein and genomic level. In contrast, this muscle typically demonstrated changes in genes associated with cell cycle regulation, without changes in EDL size of phenotype. Together, these results demonstrate different adaptation processes between the slow-twitch soleus and the fast-twitch EDL muscle, although both demonstrate changes mainly at the regulatory level.