Role of estrogen on skeletal muscle mitochondrial function in ovariectomized rats: a time course study in different fiber types

Abstract

Postmenopausal women are prone to develop obesity and insulin resistance, which might be related to skeletal muscle mitochondrial dysfunction. In a rat model of ovariectomy (OVX), skeletal muscle mitochondrial function was examined at short- and long-term periods after castration. Mitochondrial parameters in the soleus and white gastrocnemius muscle fibers were analyzed. Three weeks after surgery, there were no differences in coupled mitochondrial respiration (ATP synthesis) with pyruvate, malate, and succinate; proton leak respiration; or mitochondrial reactive oxygen species production. However, after 3 wk of OVX, the soleus and white gastrocnemius muscles of the OVX animals showed a lower use of palmitoyl-carnitine and glycerol-phosphate substrates, respectively, and decreased peroxisome proliferator-activated receptor-γ coactivator-1α expression. Estrogen replacement reverted all of these phenotypes. Eight weeks after OVX, ATP synthesis was lower in the soleus and white gastrocnemius muscles of the OVX animals than in the sham-operated and estrogen-treated animals; however, when normalized by citrate synthase activity, these differences disappeared, indicating a lower muscle mitochondria content. No differences were observed in the proton leak parameter. Mitochondrial alterations did not impair the treadmill exercise capacity of the OVX animals. However, blood lactate levels in the OVX animals were higher after the physical test, indicating a compensatory extramitochondrial ATP synthesis system, but this phenotype was reverted by estrogen replacement. These results suggest early mitochondrial dysfunction related to lipid substrate use, which could be associated with the development of the overweight phenotype of ovariectomized animals.

Time since menopause and skeletal muscle estrogen receptors, PGC-1α, and AMPK

“…33,34 Impairment in skeletal muscle mitochondrial content and oxidation after ovariectomy in rodents further suggest a role for estrogens. 35 Importantly, recent studies of muscle-specific ERα knockout (αMERKO) mice demonstrated a role for skeletal muscle ERα on mitochondrial function and metabolic homeostasis. 16 The impaired glucose homeostasis observed in the αMERKO mice was paralleled by abnormal mitochondrial morphology, impaired mitochondrial fission dynamics, and overexpression of reactive oxygen species in skeletal muscle.…”

Estradiol stimulates mitochondrial biogenesis and adiponectin expression in skeletal muscle

“…Mitochondrial function and the response to oxidative stress can be strongly affected by fiber composition (Anderson & Neufer 2006, Picard et al 2008, 2012. Ovariectomy has been reported to modify muscle contractile properties, phenotype, metabolism, and force-generating capacity (Moran et al 2006, Liu et al 2009c, whereas estradiol replacement reverses these alterations (Moran et al 2007, Liu et al 2009b, Cavalcanti-de-Albuquerque et al 2014. In this sense, it is not possible to rule out the hypothesis that the changes observed in white gastrocnemius mitochondrial function and oxidative stress response from OVX and OVXCE 2 rats are mediated by a change in fiber metabolism or phenotype; further studies would be necessary.…”

Mitochondrial activity and dynamics changes regarding metabolism in ageing and obesity

“…Low levels of oestrogens decrease PGC1α expression indicating a putative decrease in mitochondrial biogenesis (Cavalcanti-de-Albuquerque et al, 2014).…”

“…Changes in oestrogens during ageing can also affect directly the activity of regulators of mitochondria. In rats, a model of menopause by using ovariectomization suggested that reduction of oestrogens produced the decrease of PGC1α expression and the reduction of β-oxidation in muscle (Cavalcanti-de-Albuquerque et al, 2014). This suggests that an oestrogendependent effect can induce accumulation of fat and probably insulin resistance in muscle.…”