REGULATION OF C-SKI TRANSGENE EXPRESSION IN DEVELOPING AND MATURE MICE

The control of c-ski transgene expression and muscle hypertrophy have been investigated in transgenic mice. In adult animals, the level of t ransgene expression is linked to the specialized phenotype of individu al muscles, high levels occur in fast muscles and significantly lower levels in muscles with high metabolic activity (diaphragm, soleus). Th ese findings have led us to propose that a threshold must be passed be fore ski-induced growth can occur. We now show that within fast muscle s, induced hypertrophy uniquely involves IIb fibers. This pattern of e xpression is under development control; levels of c-ski mRNA are low i n all muscles at birth. In the diaphragm, there is a sevenfold increas e in c-ski message levels between 5 d and maturity. By contrast, in fa st extensor digitorum longus and anterior tibial muscles, there is a 2 4-fold increase in levels between 5 and 12 d postpartum. Muscle hypert rophy and antibody staining for c-ski protein in myofiber nuclei emerg e concurrently. This pattern of c-ski expression parallels the appeara nce of IIb myosin heavy chain transcripts (Wydert et al., 1987) and di fferentiation of IIb fibers, suggesting that amplification of c-skim R NA levels is linked to the development of IIb fiber specialization. Ma nipulations that are known to perturb IIb fiber development, neonatal denervation, and neonatally induced hypothyroidism inhibit high levels of c-ski expression and hypertrophy. In the adult fast EDL, denervati on leads to rapid atrophy of IIb fibers and a significant decline in l evels of c-ski mRNA. The results suggest that the environment of diffe rentiated IIb fibers permits the expression of high levels of c-ski mR NA and this, in turn, induces hypertrophy.