ENHANCED EXPRESSION OF MYOGENIC REGULATORY GENES IN AGING SKELETAL-MUSCLE

MyoD, myogenin, myf-5, and MRF4, belonging to the family of basic heli x-loop-helix (bHLH) myogenic regulatory factors (MRFs), control muscle cell differentiation, in concert with other transcription factors suc h as MEF-2, yet their role in age-related skeletal muscle alteration h as not been addressed. We here report that MyoD and myogenin transcrip ts are expressed at high levels in the hind limb muscles of newborn mi ce and their level of expression continuously declines throughout post natal life to become virtually undetectable in the adult mouse. Howeve r, these transcripts are again expressed at high levels in the muscles of older mice. MRF4 transcript, on the other hand, is present at a co nstant level throughout the life span of the animal. Conversely, the e xpressions of myf-5 and MEF-2C, components of the autoregulatory loop for the activation of bHLH gene expression, conspicuously increase in adult and senile muscle. In order to establish whether these transcrip ts are functioning in the aged muscle we investigated the expression o f bHLH inhibitory factor Id mRNA showing that it does not present sign ificant changes during aging. Immunofluorescence analysis with an anti -myogenin antibody revealed nuclear accumulation of the protein in the muscle fibers of old, but not of adult, mice. Muscle-specific genes t ransactivated by MyoD and myogenin such as AChR, MLC, and MCR are also up-regulated during aging, albeit at a lower level. Significant chang es in the size and ratio of type I/type II fibers are detectable in se nile muscle. These findings show that all members of the MRF family ar e expressed to a high extent and are likely active in senile muscle. I t is conceivable that these changes might operate as a compensatory me chanism in maintaining the expression of differentiated muscle product s in senile muscle at a steady-state level. (C) 1995 Academic Press, I nc.