Physiological requirements for mitochondrial respiration change during fetal and postnatal development of cardiac and skeletal muscle, particularly after the abrupt transition from the hypoxic fetal environment to the oxygen-rich milieu of the neonate. This study defines the pattern of expression of nuclear genes encoding the muscle-specific (H) and non-muscle-specific (L) isoforms of cytochrome oxidase (COX) subunit VIa during pre- and postnatal development of striated muscles in the mouse. In the early embryo, COX VIa-L was the predominant isoform expressed in all tissues. COX VIa-H mRNA was detectable as early as day 8 postcoitum (pc) in the heart, but not until gestational day 14 in skeletal myofibers of the tongue, diaphragm, and other skeletal muscles. At late fetal stages up until birth (days 16-18 pc), COX VIa-L and COX VIa-H were both expressed in striated myocytes, although the L form remained the dominant isoform. In postnatal animals, however, expression of COX VIa-H increased whereas COX VIa-L decreased in a reciprocal manner. Activation of the COX VIa-H gene also was observed during differentiation of nurine myogenic cells in culture and was followed by diminished expression of the COX VIa-L isoform in maturing myotubes, as in the intact animal. We conclude that regulation of nuclear genes encoding subunits of COX is a component of the developmental programs that govern cardiac and skeletal muscle differentiation and maturation in the mammalian fetus and neonate. COX VIa-L, the predominant isoform in all fetal tissues, is gradually replaced by the muscle-specific H isoform in both cardiac and skeletal muscles, although this transition is not complete until after birth.