Glucocorticoid maturation of mitochondrial respiratory capacity in skeletal muscle before birth.

K L Davies,E J Camm,O R Vaughan,D J Smith,A J Forhead,A J Murray,A L Fowden

doi:10.1530/joe-21-0171

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.

Highlights

In adults, glucocorticoids are stress hormones with metabolic actions on a wide range of tissues that maintain functions critical to survival in adverse environmental conditions and during normal physiological challenges to homeostasis-like exercise and pregnancy (Picard et al 2018, Bartho et al 2020, Casuro & Huertus 2020)
AX prevented the normal prepartum rise in fetal cortisol concentrations; the mean value in AX fetuses was significantly lower than the concentrations in shamoperated controls at 144 dGA and similar to control values at the earlier gestational ages (Fig. 1A)
Fetal plasma T3 concentrations were significantly higher in cortisol – than saline-infused fetuses but were not significantly affected by AX, values had a tendency to be lower in the AX than sham-operated fetuses (P = 0.057, Table 2)

Summary

Introduction

Glucocorticoids are stress hormones with metabolic actions on a wide range of tissues that maintain functions critical to survival in adverse environmental conditions and during normal physiological challenges to homeostasis-like exercise and pregnancy (Picard et al 2018, Bartho et al 2020, Casuro & Huertus 2020). Many of these functions require energy in the form of ATP, which is produced mainly by oxidative phosphorylation (OXPHOS). Glucocorticoids have been shown to influence many of these regulatory processes in mitochondria of several adult tissues, including skeletal muscle (Djouadi et al 1994, Rachamim et al 1995, Weber et al 2002, Du et al 2009)

Methods

Results

Conclusion