Making Muscle after Menopause

While testosterone has a reputation as the hormone that strengthens muscles, in women that role belongs to estrogen, University of Minnesota researchers have discovered.

In a paper published in the journal Cell Reports, the team shows that muscle stem cells start to disappear when estrogen levels decline. The repair and rebuilding of skeletal muscles depends on a specific population of stem cells—called satellite cells—found in muscle tissue, and the researchers show these cells require estrogen to function optimally in females. Unfortunately, levels of estrogen decline severely during menopause in humans. The Minnesota group shows that the hormone exerts its effects through a protein called estrogen receptor alpha, which combines with incoming estrogen and guides it into the satellite cell nucleus. There, they found, estrogen suppresses genes that would otherwise cause the cells to self-destruct.

“Our work in mice shows that sufficient levels of both estrogen and its receptor in satellite cells are necessary to keep satellite cells healthy, allowing muscles to repair after injury,” said co-senior author Dawn Lowe, PhD, a professor in the Physical Therapy Division, Department of Rehabilitation Medicine. “And with collaborators in Finland we found that in women, the population of muscle satellite cells dwindled sharply at menopause in correlation with declines in blood estrogen levels.”

Estrogen replacement therapy for menopausal symptoms can help maintain muscle health. But using it to treat weakening muscles may unnecessarily raise the risk of cancer due to estrogen’s effects on tissues such as those of the breast and endometrium. Today the search is on for a drug that can deliver the estrogen signal to muscle but not to reproductive tissues.

A drug called BZA was known to interact with estrogen receptors in a way that doesn’t affect breast or endometrial tissue, but whether it would do what estrogen does for muscle was not known. Lowe and her colleagues showed that in muscle, the drug mimics the beneficial effects of estradiol, the major form of human estrogen.

Therefore, BZA could potentially shield aging women from muscle stem cell decline due to menopause, without the risks associated with conventional hormone replacement therapy.

A First in the Field

Here, briefly, is how the researchers made their discoveries.

When they removed a mouse’s ovaries, and thus her estrogen supply, satellite cell populations plummeted and leg muscles showed poor recovery of strength following minor injury. Estradiol treatment reversed both conditions, demonstrating the association between satellite cells and a muscle’s regenerative capabilities, as well as estradiol’s central role. 

Mice in which the team had disabled the gene for the estrogen receptor showed 30 to 60 percent drops in satellite cell numbers across five different muscles. The surviving cells had severe difficulty reproducing themselves and generating new muscle cells.

The human work was a pilot study with Finnish women. In muscle biopsies taken shortly before and after the transition to menopause, numbers of satellite cells correlated strongly with changing serum estradiol levels. 

“This is the first work to show that estrogen deficiency affects the number as well as the function of satellite cells,” said Lowe. The team’s success came about in part because they built on “a history of innovation in the area of mouse models and methodologies,” said co-senior author Michael Kyba, PhD, a professor in the University’s Stem Cell Institute and Department of Pediatrics. Case in point: Kyba and his colleagues had developed a mouse line in which the activities of satellite cells could be tracked.

The Other Half

“It’s well known that both women and men lose muscle mass with aging,” said Lowe. “Muscles are continually injured throughout life, so it’s important that they maintain the capacity to repair themselves and generate force. Estradiol and the estrogen receptor are critical for this to happen in females. We do not know their importance, if any, in males.

“A lot of classical aging work was done in male rodent models, because the timing of ovarian senescence in females is variable, making it harder to study aging female mice. Thus, it’s well known that male sex hormones promote muscle health, but we have been in the dark about what happens when females age. What estrogen does in women in terms of reproduction has been known for decades. Now we’re learning what estrogens do in women’s muscles.”

The study was funded by the National Institute on Aging and the National Institute of Arthritis and Musculoskeletal and Skin Diseases.