Estrogen’s Critical Role in Muscle Insulin Sensitivity and Preventing Metabolic Syndrome  

breast carcinoma tissue stained for estrogen receptor

The estrogen receptor plays an important role in maintaining the health of skeletal muscle mitochondria. This process attenuates insulin resistance. Insulin resistance leads to a downstream cascade towards metabolic syndrome and diabetes mellitus. On the right is a breast carcinoma tissue stained for estrogen receptor.

Estrogen is well known to play a protective role against a variety of diseases. Estrogen maintains bone health preventing osteoporosis, protects against metabolic syndrome and likely plays a role vascular health, decreasing the risk of cardiovascular disease. These physiologic effects led estrogen to be deemed the youth hormone. For decades, postmenopausal women were prescribed estrogen to maintain bone health and prevent cardiovascular disease. However, this practice, commonly called hormone replacement therapy (HRT), fell out of favor in 2002 when new studies showed all-cause mortality was actually higher in postmenopausal women on HRT. A recent study published in Science Translational Medicine sheds light on an additional organ system that estrogen acts on: skeletal muscle. This study found that the estrogen receptor is essential for maintaining skeletal muscle mitochondria with the downstream consequences of increased reactive oxygen species clearance and insulin sensitivity-loss of which plays an essential role in the pathogenesis of type II diabetes mellitus (Skeletal muscle action of estrogen receptor α is critical for the maintenance of mitochondrial function and metabolic homeostasis in females, 2016. Ribas, et al.).

Skeletal muscle plays an important part in the regulation of blood glucose levels. In response to insulin, skeletal muscle takes up glucose via GLUT4 channels. When the skeletal muscle becomes unresponsive to insulin (insulin insensitivity) the muscle fails to take up glucose from the blood resulting in the elevated blood glucose levels characteristic of diabetes. Metabolic syndrome is a precursor to diabetes mellitus and includes elevated LDL cholesterol, central obesity, reduced glucose tolerance and high blood pressure.

Mitochondria are the powerhouses of most cells in the body (red blood cells being the notable exception). These organelles generate energy for the cell in the form of ATP. In any cell, damage to mitochondria can result in reactive oxygen species and possibly irreversible cell damage. Mature skeletal muscle cells do not replicate and rely on healthy mitochondria to supply their aerobic energy demands. Although muscle fibers do not replicate during our adult lives, their mitochondria must replicate to avoid damage over the myofiber lifespan. With this background on mitochondria, skeletal muscle and metabolic syndrome lets investigate the role of estrogen.

Muscle estrogen receptor expression is lower in women with metabolic syndrome

In the aforementioned study, premenopausal women with metabolic syndrome were found to have lower levels of skeletal muscle estrogen receptors. This finding of reduced skeletal muscle estrogen receptors was also found in obese mice. The findings in postmenopasaul women are shown in the figure to the right. The next step for the researchers was to determine the mechanism responsible for linking metabolic syndrome to low skeletal muscle estrogen receptor levels.

The researchers selectively knocked out the estrogen receptor from skeletal muscle in mice to investigate the mechanism by which low estrogen receptors in skeletal muscle are associated with metabolic syndrome. They called these skeletal muscle estrogen receptor deficient mice MERKO (Muscle Estrogen Receptor Knock Out) mice. MERKO mice demonstrated a smorgasbord of health problems including decreased glucose tolerance and a depressed muscle insulin response. Recall that insulin resistance plays an essential role in the pathogenesis of diabetes by impairing glucose uptake into skeletal muscle when blood blood glucose levels are elevated (i.e. after a meal). In addition, MERKO mice displayed increased muscle inflammation and higher levels of lipids or fat in the muscle. Muscle endurance was diminished in mice without a skeletal muscle estrogen receptor, although peak tension remained the same.

Muscle mitochondrial damage in the MERKO mice suggests that estrogen may play an important role in maintaining muscle mitochondria health. Mitochondria function was reduced as measured with several tests including cellular oxidative capacity, reactive oxygen species (ROS) scavenging capacity and calcium handling. Furthermore, damage to the mitochondria in MERKO mice led to higher levels of free radicals in the muscle cells of MERKO mice.

mitochondrial DNA replication is reduced in muscle lacking estrogen receptor resulting in altered mitochondrial morphology.

Apparently, skeletal muscle estrogen receptors are necessary for smooth mitochondrial DNA (mtDNA) replication during mitochondrial turnover. Although most DNA in humans, or any eukaryotic organism for that matter, is stored in the nucleus, the mitochondria retains a small genome that produces proteins necessary for mitochondrial function. Increased mitochondrial DNA mutations and decreased mtDNA replication resulted in muscle mitochondria with altered morphology. The mitochondria shape and size discrepancy between normal (Control) and muslce estrogen receptor deficient (MERKO) mice can be seen in the electron microscope images of mouse muscle above.

Impaired mitochondria in skeletal muscle does not directly explain why these estrogen receptor deficient myofibrils exhibited impaired insulin sensitivity. Interestingly, the researchers identified a known oxidative stress response gene that was up regulated in the estrogen deficient mouse muscle cells. The gene, Rcan1, is a known inhibitor of the protein phosphatase calcineurin. Calcineurin activity is important for mitochondria fission and autophagy. Rcan1 also directly increases a DNA polymerase for mtDNA replication. Besides impairing mitochondria, Rcan1 decreases insulin sensitivity through its inhibitory action on calcineurin. Confirming its importance in the muscle estrogen receptor deficient pathogenesis of metabolic syndrome, Rcan1 levels were increased in the skeletal muscle of premenopausal women with metabolic syndrome. 

As an aside, calcineurin is a common immunosuppression target. Prograf (tacrolimus) and Sandimmune or Neoral (cyclosporine) are calcineurin inhibitors commonly used for suppressing the immune system in organ transplant recipients and patients with autoimmune disease. A common adverse effect of these immunosuppressant drugs is, you guessed it, metabolic syndrome. Calcineurin inhibitor drugs are essentially synthetic versions of Rcan1.

In conclusion, it appears estrogen receptors play an important role in maintaining skeletal muscle longevity through their action on mitochondrial health and function. This is important because a deficiency of skeletal muscle estrogen receptors leads to muscle inflammation and impaired insulin action. Insulin resistance is an essential component in the pathogenesis of type II diabetes mellitus and helps mediate metabolic syndrome. Skeletal muscle estrogen receptors may represent a target for treating metabolic syndrome.

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