DEVELOPMENTAL REGULATION OF CYTOCHROME-OXIDASE SUBUNIT VIA ISOFORMS IN CARDIAC AND SKELETAL-MUSCLE

Physiological requirements for mitochondrial respiration change during fetal and postnatal development of cardiac and skeletal muscle, parti cularly after the abrupt transition from the hypoxic fetal environment to the oxygen-rich milieu of the neonate. This study defines the patt ern of expression of nuclear genes encoding the muscle-specific CH) an d 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 embyro, COX VIa-L was the predominant isoform expr essed 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 skel etal myofibers of the tongue, diaphragm, and other skeletal muscles. A t 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 re mained the dominant isoform. In postnatal animals, however, expression of COX VIa-H increased whereas COX VIa-L decreased in a reciprocal ma nner. Activation of the COX VIa-H gene also was observed during differ entiation of murine myogenic cells in culture and was followed by dimi nished expression of the COX VIa-L isoform in maturing myotubes, as in the intact animal. We conclude that regulation of nuclear genes encod ing subunits of COX is a component of the developmental programs that govern cardiac and skeletal muscle differentiation and maturation in t he mammalian fetus and neonate. COX VIa-L, the predominant isoform in all fetal tissues, is gradually replaced by the muscle-specific H isof orm in both cardiac and skeletal muscles, although this transition is not complete until after birth.