Skeletal muscle mitochondria: A potential target for postmenopausal hormone replacement therapy

In this issue of Acta Physiologica, Kleis-Olsen et al.¹ investigated the association of postmenopausal hormone replacement therapy (HRT) with skeletal muscle mitochondrial function measured using biopsy samples from human vastus lateralis muscle. They reported that postmenopausal women who received a combination of estradiol and progestin had higher mitochondrial respiratory capacity in the skeletal muscle compared with non-treated postmenopausal women. Since estrogen deficiency due to menopause is associated with skeletal muscle dysfunction characterized by muscle weakness and muscle loss,² it is clinically relevant to examine whether HRT may prevent menopause-related impairment of skeletal muscle energy metabolism.

Menopause is defined by the permanent cessation of menstruation occurred at an average age around 50 years. It is natural course of reproductive aging for women and the transition into menopause is characterized by a significant reduction in circulating estrogen levels. Menopause may accelerate age-related functional decline with both physiological and psychological symptoms and adversely affect cardiovascular and musculoskeletal health. Because women live longer than men, women are more likely to experience negative changes in skeletal muscle, leading to reduced quality of life with increased morbidity and mortality.³

HRT is a pharmacological therapy that contains ovarian hormones (estrogen with or without progesterone), prescribed to manage menopausal symptoms. Although estrogen alone is enough to treat menopausal symptoms, it may increase the risk of cancer of the uterus (endometrial cancer), and therefore, progesterone is usually added to estrogen to reduce the risk of endometrial cancer back to normal. HRT has multiple health benefits, including reduced risk of cardiovascular diseases and all-cause mortality as well as relief of menopausal symptoms.³ Estrogen is considered to be a key regulator of whole-body energy homeostasis.⁴ Compared with other organs, skeletal muscle exhibits higher metabolic flexibility in response to hormone stimulation as well as exercise and environmental factors.⁵ However, the effect of HRT on skeletal muscle mitochondria in postmenopausal women remains fully unclear.

Previous studies have shown the effects of estrogen on skeletal muscle mitochondria in ovariectomized rodents (animal models of menopause),^{6, 7} but Kleis-Olsen et al. for the first time demonstrated the association of postmenopausal HRT with increased mitochondrial respiratory capacity in the skeletal muscle in human.¹ Middle-aged postmenopausal women who had received a combination of estradiol and progestin for 3.6 years on average were participated in their cross-sectional study. Compared with matched non-treated postmenopausal women (i.e., controls), mitochondrial oxidative phosphorylation (OXPHOS) capacity with complex I- or complex I + II-linked substrates normalized to wet weight of permeabilized muscle fibers was higher in hormone-treated postmenopausal women, irrespectively of whether the participants' muscle fibers were obtained at rest or immediately after exercise. However, the difference in muscle mitochondrial OXPHOS capacity between hormone-treated and non-treated women was diminished when it was normalized to mitochondrial citrate synthase (CS) activity, a marker of mitochondrial content, indicating that the higher mitochondrial OXPHOS capacity normalized to wet weight of permeabilized muscle fibers in hormone-treated women might be attributed to increased mitochondrial content. Indeed, hormone-treated women had a higher muscle CS activity compared with non-treated women. In addition, there was no difference in mitochondrial hydrogen peroxide emission per mitochondrial content in the skeletal muscle between hormone-treated and non-treated women.

Estrogen may be directly involved in muscle metabolism via estrogen receptors (ERs) as well as indirect mechanism including somatotropic axis that consists of growth hormone and insulin-like growth factors.³ In human skeletal muscle, at least two ER isoforms, ERα and ERβ, have been identified.⁸ After estradiol, the predominant circulating estrogen in human, binds to the ERs in the cytosol, the estradiol/ER complex translocates into the nucleus, leading to transcription of nuclear DNA related to mitochondrial biogenesis including peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), nuclear respiratory factor (NRF), and mitochondrial transcriptional factor A (TFAM).⁵ In addition, the ERs may bind to mitochondrial DNA (mtDNA) and be involved in estrogen-induced expression of mtDNA and mitochondrial respiratory proteins.⁵ Although precise mechanism that underlies beneficial effect of estrogen on skeletal muscle mitochondria is not still well understood, estradiol supplementation might contribute to the higher mitochondrial respiratory capacity with increased mitochondrial content in the skeletal muscle of postmenopausal women at least in part via muscle-specific ERs.

In contrast, it seems controversial whether progesterone has positive or inhibitory effect on skeletal muscle mitochondria.⁹ A previous study showed that administration of progesterone alone in the medium during incubation of muscle fibers obtained from non-menopausal healthy women decreased mitochondrial OXPHOS capacity, but this decrease was diminished when estrogen was added to progesterone.¹⁰ In the study by Kleis-Olsen et al.¹ plasma levels of estradiol were higher in hormone-treated postmenopausal women but plasma progesterone levels were comparable between hormone-treated and non-treated postmenopausal women, suggesting that the higher muscle mitochondrial respiratory capacity in postmenopausal women undergoing HRT might be largely attributed to supplementation of estrogen rather than progesterone.

In conclusion, the work by Kleis-Olsen et al. enhances our understanding of mitochondrial adaptation to HRT in the skeletal muscle in postmenopausal women. Given that this is a cross-sectional study, randomized clinical trials are further warranted to provide stronger evidence on the effect of postmenopausal HRT on skeletal muscle mitochondrial function.

Takashi Yokota: Conceptualization; writing-original draft.

The author has no conflict of interest to disclose.