Glucocorticoid maturation of mitochondrial respiratory capacity in skeletal muscle before birth

Abstract

In adults, glucocorticoids act to match the supply and demand for energy during physiological challenges, partly through actions on tissue mitochondrial oxidative phosphorylation (OXPHOS) capacity. However, little is known about the role of the natural prepartum rise in fetal glucocorticoid concentrations in preparing tissues for the increased postnatal energy demands. This study examined the effect of manipulating cortisol concentrations in fetal sheep during late gestation on mitochondrial OXPHOS capacity of two skeletal muscles with different postnatal locomotive functions. Mitochondrial content, biogenesis markers, respiratory rates and expression of proteins and genes involved in the electron transfer system (ETS) and OXPHOS efficiency were measured in the biceps femoris (BF) and superficial digital flexor (SDF) of fetuses either infused with cortisol before the prepartum rise or adrenalectomised to prevent this increment. Cortisol infusion increased mitochondrial content, biogenesis markers, substrate-specific respiration rates and abundance of ETS Complex I and adenine nucleotide translocator (ANT1) in a muscle-specific manner that was more pronounced in the SDF than BF. Adrenalectomy reduced mitochondrial content and expression of PGC1α and ANT1 in both muscles, and ETS Complex IV abundance in the SDF near term. Uncoupling protein gene expression was unaffected by cortisol manipulations in both muscles. Gene expression of the myosin heavy chain isoform, MHCIIx, was increased by cortisol infusion and reduced by adrenalectomy in the BF alone. These findings show that cortisol has a muscle-specific role in prepartum maturation of mitochondrial OXPHOS capacity with important implications for the health of neonates born pre-term or after intrauterine glucocorticoid overexposure.

Developmental programming of mitochondrial substrate metabolism in skeletal muscle of adult sheep by cortisol exposure before birth

“…Neither CS activity nor mitochondrial OXPHOS capacity normalised to CS activity were affected by cortisol infusion in the fetuses, regardless of the specific substrate or muscle, consistent with previous measurements of CS activity per mg BF protein in cortisol-infused fetal sheep. 22 However, by adulthood, PCM-supported respiration was 60-70% higher than control values in the ST of animals that received cortisol as fetuses. Fetal exposure to higher than normal levels of cortisol in late gestation can, therefore, have longer term effects on mitochondrial substrate metabolism and may enhance the capacity of adult sheep to use fatty acids for OXPHOS in selective muscles.…”

Cortisol Regulates Cerebral Mitochondrial Oxidative Phosphorylation and Morphology of the Brain in a Region-Specific Manner in the Ovine Fetus

“…The administration of potent synthetic glucocorticoids during rodent pregnancy has also been shown to increase the mitochondrial content in the fetal lung [ 26 ] and kidney [ 27 ], and alter the abundance of mitochondrial proteins in fetal tissues near term, such as the brain [ 28 ], kidney [ 27 ] and heart [ 29 ]. Recent studies have also shown that variations in the endogenous cortisol concentration affect CS activity in ovine fetal skeletal muscle [ 30 ].…”

Metabolic Consequences of Glucocorticoid Exposure before Birth

“…Adult mitochondria are dynamic organelles that respond to changes in energy demands by biogenesis and alterations in the electron transfer system (ETS) complexes and other proteins regulating ATP synthesis, including those supporting oxidation of specific substrates [ 98 ]. Glucocorticoids are known to influence many of these regulatory processes in adult tissues and recent studies have shown that they also have an important role in the normal prepartum maturation of mitochondrial OXPHOS capacity in cardiac and skeletal muscle [ 74 , 99 , 100 , 101 , 102 ].…”

“…Maternal dexamethasone administration to pregnant ewes near term also increases the abundance of mitochondrial ETS and uncoupling proteins in perirenal adipose tissue of their fetuses in line with the need for non-shivering thermogenesis at birth [ 56 , 73 ]. Similarly, direct cortisol infusion into fetal sheep in late gestation increases mitochondrial content and respiratory capacity of skeletal muscle in a manner that depends on the specific oxidative substrate and muscle studied [ 74 ]. Furthermore, raising fetal corticosterone indirectly in fetal rats in late gestation by ligating the uterine artery also increases expression of several ETS complexes in a range of fetal tissues two days later [ 104 , 105 ].…”

“…Furthermore, raising fetal corticosterone indirectly in fetal rats in late gestation by ligating the uterine artery also increases expression of several ETS complexes in a range of fetal tissues two days later [ 104 , 105 ]. Conversely, preventing the natural prepartum rise in fetal GC pharmacologically or by fetal adrenalectomy or gene deletion in the adrenal GC biosynthetic pathway abolishes the normal increase in mitochondrial content in several tissues of fetal sheep and rodents close to term [ 74 , 82 , 102 ].…”