AbstractWe have previously demonstrated that p100H mutant mice, which lack a functional Sox6 gene, exhibit skeletal and cardiac muscle degeneration and develop cardiac conduction abnormalities soon after birth. To understand the role of Sox6 in skeletal muscle development, we identified muscle‐specific genes differentially expressed between wild‐type and p100H mutant skeletal muscles and investigated their temporal expression in the mutant muscle. We found that, in the mutant skeletal muscle, slow fiber and cardiac isoform genes are expressed at significantly higher levels, whereas fast fiber isoform genes are expressed at significantly lower levels than wild‐type. Onset of this aberrant fiber type‐specific gene expression in the mutant coincides with the beginning of the secondary myotube formation, at embryonic day 15–16 in mice. Together with our earlier report, demonstrating early postnatal muscle defects in the Sox6 null‐p100H mutant, the present results suggest that Sox6 likely plays an important role in muscle development. Developmental Dynamics 234:301–311, 2005. © 2005 Wiley‐Liss, Inc.