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Developmental regulation of cytochrome oxidase subunit VIa isoforms in cardiac and skeletal muscle
W J Parsons1, R S Williams, J M Shelton
1Department of Internal Medicine, University of Texas Southwestern Medical Center at Dallas 75235, USA.
Insights
Mitochondrial respiration adapts to oxygen changes after birth. The study tracks cytochrome oxidase (COX) subunit VIa isoforms (L and H) in mouse muscle development, finding a shift from the L to the H form postnatally.
Area of Science:
- Developmental Biology
- Mitochondrial Physiology
- Molecular Genetics
Background:
- Mitochondrial respiration requirements change significantly from fetal to postnatal life.
- The transition from a hypoxic fetal environment to an oxygen-rich neonatal environment impacts muscle physiology.
- Cytochrome oxidase (COX) is crucial for mitochondrial respiration, with different isoforms (L and H) potentially playing distinct roles.
Purpose of the Study:
- To define the expression patterns of nuclear genes encoding muscle-specific (COX VIa-H) and non-muscle-specific (COX VIa-L) isoforms of cytochrome oxidase subunit VIa.
- To investigate these expression patterns during pre- and postnatal development of cardiac and skeletal muscles in mice.
- To understand the role of COX subunit VIa isoform regulation in muscle differentiation and maturation.
Main Methods:
- Analysis of COX VIa-L and COX VIa-H mRNA expression during mouse embryonic and postnatal development.
- Examination of gene expression in various striated muscles including heart, tongue, and diaphragm.
- In vitro studies using cultured myogenic cells to observe isoform expression during differentiation.
Main Results:
- COX VIa-L was the predominant isoform in early embryonic tissues.
- COX VIa-H expression was detected later in development, initially in the heart and later in skeletal muscles.
- During late fetal stages, both isoforms were present, with L dominant; postnatally, COX VIa-H expression increased reciprocally as COX VIa-L decreased.
- Similar reciprocal changes were observed in cultured myogenic cells during differentiation.
Conclusions:
- Regulation of nuclear genes encoding COX subunits is integral to cardiac and skeletal muscle differentiation and maturation.
- The muscle-specific COX VIa-H isoform gradually replaces the ubiquitous COX VIa-L isoform in striated muscles during development.
- This isoform transition, crucial for adapting to postnatal oxygen levels, is not fully completed until after birth.
Abstract:
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.