Differential expression of muscle regulatory factor genes in normal and denervated adult rat hindlimb muscles.

Skeletal muscle represents an excellent model system in which to examine regulatory mechanisms that modulate gene expression in the mature adult organism. Individual muscle fibers can be categorized as fast- or slow-twitch based upon several physiological and molecular criteria, including metabolic enzyme activity and contractile protein isoforms. Each property can be influenced by a variety of factors such as changes in motor neuron activity or alterations in hormone levels, although the molecular pathways by which environmental factors affect gene expression remain largely unknown. As a first step in identifying potential regulators of fiber-type diversity, the expression patterns of four basic/helix-loop-helix muscle regulatory factors (MRFs), referred to as MyoD, myogenin, Myf-5, and MRF4, were examined in normal adult rat muscles which differed in their phenotypic properties. As expected, all four MRFs were expressed at detectable levels in the muscles studied. However, different muscles accumulated different proportions and combinations of MRF transcripts. For example, myogenin expression was maximally detected in slow-twitch muscles whereas MyoD transcripts were found predominantly in muscles exhibiting a fast-twitch phenotype. Induced phenotypic changes in two fast-twitch muscles via denervation lead to a large and rapid increase in transcript levels of all four MRFs as early as 24 hr following denervation, with myogenin transcripts approaching 150-200-fold higher levels than innervated contralateral muscles within 7 days. These results suggest that myogenin, as well as the other three MRFs, may be involved in both the initial establishment as well as maintenance of fiber-type diversity in the developing organism.