ABSTRACT
The objective of this report was to analyse a potential role for FGF6 in muscle resistance to mechanical stress. Normal or regenerating muscles of FGF6 (-/-) mice versus wild-type mice were submitted to different protocols of damaging eccentric contractions (eccentric electrostimulation and intermittent downhill exercise). Then muscular structural properties were analysed by histological and immunochemistry techniques to evaluate the post-injury muscle recovery; their muscle contractile parameters (maximal tetanic force, kinetics properties and fatigue resistance) were assessed. The absence of FGF6 causes (1) a fast-to-slow myofibre type switch in adult control and regenerating Tibialis anterior (TA) muscle; (2) muscle weakness in regenerating muscles in animals submitted to eccentric exercise protocols due to aberrant extensive necrotic zones. These observations point out a crucial and unexpected role for FGF6 in muscle integrity and muscle protection against mechanical stress.
Subject(s)
Fibroblast Growth Factor 6/physiology , Muscle Contraction/genetics , Muscle Strength/genetics , Physical Stimulation , Stress, Mechanical , Animals , Fibroblast Growth Factor 6/genetics , Genetic Predisposition to Disease , Mice , Mice, Inbred C57BL , Mice, Knockout , Muscle Contraction/physiology , Muscle Fibers, Skeletal/metabolism , Muscle Fibers, Skeletal/physiology , Muscle Strength/physiology , Muscle, Skeletal/metabolism , Muscle, Skeletal/physiology , Muscular Diseases/genetics , Regeneration/genetics , Regeneration/physiologyABSTRACT
This study establishes a causal link between the limitation of myofibre transitions and modulation of calcineurin activity, during different exercise paradigms. We have designed a new swimming-based training protocol in order to draw a comparison between a high frequency and amplitude exercise (swimming) and low frequency and amplitude exercise (running). We initially analysed the time course of muscle adaptations to a 6- or 12-week swimming- or running-based training exercise program, on two muscles of the mouse calf, the slow-twitch soleus and the fast-twitch plantaris. The magnitude of exercise-induced muscle plasticity proved to be dependent on both the muscle type and the exercise paradigm. In contrast to the running-based training which generated a continuous increase of the slow phenotype throughout a 12-week training program, swimming induced transitions to a slower phenotype which ended after 6 weeks of training. We then compared the time course of the exercise-induced changes in calcineurin activity during muscle adaptation to training. Both exercises induced an initial activation followed by the inhibition of calcineurin. In the muscles of animals submitted to a 12-week swimming-based training, this inhibition was concomitant with the end of myofibre transition. Calcineurin inhibition was a consequence of the inhibition of its catalytic subunit gene expression on one hand, and of the expression increase of the modulatory calcineurin interacting proteins 1 gene (MCIP1), on the other. The present study provides the first experimental cues for an interpretation of muscle phenotypic variation control.
Subject(s)
Calcineurin/physiology , Muscle Fibers, Fast-Twitch/metabolism , Muscle Fibers, Slow-Twitch/metabolism , Physical Conditioning, Animal/physiology , Adaptation, Physiological , Animals , Calcineurin/genetics , Choline O-Acetyltransferase/metabolism , Exercise Test , Immunohistochemistry , Lactic Acid/blood , Male , Mice , Mice, Inbred CBA , Motor Activity , Motor Neurons/metabolism , Muscle, Skeletal/enzymology , Muscle, Skeletal/metabolism , Myosin Heavy Chains/metabolism , Phosphoric Monoester Hydrolases/physiology , Protein Isoforms , Proto-Oncogene Proteins c-fos/immunology , RNA, Messenger/metabolism , Running , Swimming , Time FactorsABSTRACT
Among the myogenic regulatory factors, myogenin is a transcriptional activator situated at a crucial position for terminal differentiation in muscle development. It is unclear at present whether myogenin exhibits unique specificities to transactivate late muscular markers. During Xenopus development, the accumulation of myogenin mRNA is restricted to secondary myogenesis, at the onset of the appearance of adult isoforms of beta-tropomyosin and myosin heavy chain. To determine the role of myogenin in the isoform switch of these contractile proteins, we characterized and directly compared the functional properties of myogenin with other myogenic regulatory factors in Xenopus embryos. Two distinct cDNAs related to myogenin, XmyogU1 and XmyogU2, were differentially expressed during myogenesis and in adult tissues, in which they preferentially accumulated in oxidative myofibers. Animal cap assays in Xenopus embryos revealed that myogenin, but not the other myogenic regulatory factors, induced expression of embryonic/larval isoforms of the beta-tropomyosin and myosin heavy chain genes. Only XmyogU1 induced expression of the adult fast isoform of the myosin heavy chain gene. This is the first demonstration of a specific transactivation of one set of muscle structural genes by myogenin.
