Progesterone impairs cell respiration and suppresses a compensatory increase in glucose transport in isolated rat skeletal muscle: a non-genomic mechanism contributing to metabolic adaptation to late pregnancy?

Abstract

Aims/hypothesis The aim of the study was to gain better insight into the mechanisms responsible for impaired glucose metabolism during late pregnancy. We explored the direct effects of progesterone on glucose metabolism of skeletal muscle. Methods Specimens of skeletal muscle from untreated rats were incubated with progesterone and rates of substrate fluxes through the various pathways of glucose metabolism were analysed. Results Progesterone dose-dependently reduced the rates of glucose and pyruvate oxidation (insulin-stimulated rates after 5 h of exposure to 1 and 10 μmol/l progesterone: glucose oxidation, −6±4%, NS, and −39±4%, p<0.001; pyruvate oxidation, −28±2% and −55±4%, p<0.001 each) and increased lactate release (+28±4% and +58±9%, p<0.005 each), which indicated inhibition of mitochondrial respiratory function. Impairment of cell respiration, e.g. by the specific inhibitor rotenone, is known to trigger a compensatory increase in glucose transport, but this response was blunted in the case of progesterone (change of glucose transport in response to 10 μmol/l progesterone vs 60 nmol/l rotenone, both causing a reduction in glucose oxidation by −39%: progesterone, +14±8% vs rotenone, +84±23%, p< 0.03). Further experiments dealt with the underlying mechanisms and revealed a rapid mode of action (50 μmol/l progesterone, reduction in insulin-stimulated glucose oxidation after 30 min: −29±7%, p<0.01) not affected by blockers of gene expression or the nuclear progesterone receptor. Conclusions/interpretation Progesterone inhibits cell respiration and at the same time suppresses a compensatory increase in glucose transport, causing cellular carbohydrate deficiency in isolated rat skeletal muscle. This effect is mediated by a direct, rapid and non-genomic mechanism and could contribute to pregnancy-associated changes in glucose homeostasis.

Progesterone increases skeletal muscle mitochondrial H2O2emission in nonmenopausal women

“…To clarify discrepancies in the earlier literature, the current study utilized permeabilized myofibers from women in the early follicular phase of the menstrual cycle incubated with high late-follicular phase-relevant concentrations of E2 (1.4 nM) and midluteal phase-relevant P4 (60 nM) (11,41). In agreement with the results of reports demonstrating an inhibitory effect of P4 on mitochondrial respiration in animals (13,16,20,21), we observed a significantly lower JO 2 in fibers incubated with P4 alone but not when combined with E2. In light of the results of our recent study linking mE H2O2 to skeletal muscle insulin resistance (3), the observed increase in mE H2O2 after acute ex vivo treatment with P4 and E2 ϩ P4 (but not E2) provides a potential link between the ovarian sex steroids and the reduced insulin sensitivity reported during the luteal phase of the menstrual cycle (see summary Fig.…”

“…Importantly, this was a rapid phenomenon, which persisted even when inhibitors of transcription, protein synthesis, and the nuclear progesterone receptor were included in the preparation, strongly supporting the nongenomic nature of P4 on skeletal muscle metabolism (20). Moreover, it was determined that the progesterone receptor membrane component 1, the putative cell-surface mediator of progesterone's nongenomic effects, is clearly present in rat skeletal muscle (20). Whether the membrane progesterone receptor may mediate or is necessary for the observed increase in mE H2O2 in the current study will require further research.…”

“…In their study, Gras et al (20) demonstrated inhibition of respiration in isolated muscle strips from male rats that was not matched by the expected compensatory increase in insulin-stimulated glucose transport into the tissue. Importantly, this was a rapid phenomenon, which persisted even when inhibitors of transcription, protein synthesis, and the nuclear progesterone receptor were included in the preparation, strongly supporting the nongenomic nature of P4 on skeletal muscle metabolism (20). Moreover, it was determined that the progesterone receptor membrane component 1, the putative cell-surface mediator of progesterone's nongenomic effects, is clearly present in rat skeletal muscle (20).…”

“…physiological relative to levels found in circulation; in this case, anywhere from 80 to 150 M, or over 1,000 times greater than the luteal-phase serum P4 concentration in women (41). Some insight into the rapid, nongenomic nature of late pregnancy-relevant P4 concentrations (1-50 M) on respiration and glucose metabolism was recently provided (20). In their study, Gras et al (20) demonstrated inhibition of respiration in isolated muscle strips from male rats that was not matched by the expected compensatory increase in insulin-stimulated glucose transport into the tissue.…”

“…Since then, studies examining the effects of estradiol (E2) and progesterone (P4) on mitochondrial function have employed treatment designs that increase the physiological relevancy of data supporting the inhibitory effects of sex steroids on mitochondrial respiration (20,21). Nevertheless, most studies continue to employ supraphysiological concentrations of sex steroids to investigate the nongenomic effects of female sex steroids on mitochondrial function (16,45).…”