Regulation of c-ski Transgene Expression in Developing and Mature Mice

Abstract

The control of c-ski transgene expression and muscle hypertrophy have been investigated in transgenic mice. In adult animals, the level of transgene expression is linked to the specialized phenotype of individual muscles, high levels occur in fast muscles and significantly lower levels in muscles with high metabolic activity (diaphragm, soleus). These findings have led us to propose that a threshold must be passed before ski-induced growth can occur. We now show that within fast muscles, induced hypertrophy uniquely involves IIb fibers. This pattern of expression is under development control; levels of c-ski mRNA are low in all muscles at birth. In the diaphragm, there is a sevenfold increase in c-ski message levels between 5 d and maturity. By contrast, in fast extensor digitorum longus and anterior tibial muscles, there is a 24-fold increase in levels between 5 and 12 d postpartum. Muscle hypertrophy and antibody staining for c-ski protein in myofiber nuclei emerge concurrently. This pattern of c-ski expression parallels the appearance of IIb myosin heavy chain transcripts (Wydert et al., 1987) and differentiation of IIb fibers, suggesting that amplification of c-ski mRNA levels is linked to the development of IIb fiber specialization. Manipulations 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, denervation leads to rapid atrophy of IIb fibers and a significant decline in levels of c-ski mRNA. The results suggest that the environment of differentiated IIb fibers permits the expression of high levels of c-ski mRNA and this, in turn, induces hypertrophy.