Diversité des fibres musculaires squelettiques, rôle des homéoprotéines Six

Abstract

The mechanisms by which fast/slow muscle fiber diversity emerges during mammalian development are poorly understood, although fast/slow motoneuron activity is known to be an important stimulus controlling fiber-type maintenance and transition in adults. The key role of innervation in the maintenance of the slow-phenotype of the mature adult fibers has been amply demonstrated through denervation and cross-innervation experiments, as well as by the use of various electrical stimulation paradigms. Several signaling pathways have been reported to link nerve stimulation (inducing intracellular calcium elevation) to the maintenance of the slow muscle fiber phenotype. Less is known about the transcription factors and signaling pathways responsible for the fast IIB-glycolytic phenotype. Six1 homeoprotein accumulates at higher levels in the nuclei of adult fast-type myofibers, and Six transcription complexes are far more active in fast/glycolytic fibers than in slow/oxidative fibers. Ectopic expression of Six proteins in the slow soleus muscle leads to a switch from the slow/oxidative phenotype to the fast/glycolytic phenotype, confirming the involvement of this transcriptional complex in the fast/glycolytic phenotype. We have further shown that Six homeoprotein-mutant mice exhibit an impaired capacity to generate fast-type myofibers during embryonic development, and that adult myofibers deprived of Six1 have a slower phenotype. We have also characterized the gene networks controlled by Six homeoproteins at various developmental stages and have shown that, in the adult myofiber, Six proteins control the activity of an enhancer at the fast myosin heavy chain cluster. We identified a three-element genetic partnership in which this enhancer under the control of the myogenic homeoprotein Six1, functions as a regulatory hub that controls the fast fiber phenotype. In this partnership, the enhancer positively controls the expression of both the adjacent fast myosin heavy chain (MYH) gene cluster and Linc-MYH. Linc-MYH is present only in adult fast-type skeletal myofibers, where it suppresses slow-type gene expression.