Bone To Pick: MicroRNA Contributes To Bone And Muscle Loss With Age

(Posted on Monday, December 18, 2023)

Odds are you’ve never heard of microRNAs. Even if you have, you might not care much. New research, published in Aging and Disease, might convince you otherwise: microRNA-141-3p increases with age, and alongside it a number of issues, including weakened bones, chronic inflammation, and shrinking muscle mass. The findings suggest that blocking this microRNA may be able to rescue bone, immune, and muscle health.

What are microRNAs?

Although almost all of our cells contain the same DNA, many perform vastly different functions. How? Our genes can be turned “on” or “off”. This is known as gene regulation, and determines which set of instructions —or genes— will actually be “expressed”. Different genes create different proteins, and thus shape the state and function of a cell. For example, your liver cells don’t need to send neurotransmitters, so they keep that gene “turned off”. Neurons, on the other hand, do rely on neurotransmitters to send signals, so they express the relevant genes. 

MicroRNAs are one mechanism by which gene expression is regulated; rather than intervening at the root —blocking or activating genes— they instead intervene at the protein-production stage. These tiny slivers of RNA attach to larger sequences called messenger RNA (mRNA), which provide the genetic information used as a blueprint for the production of proteins. Once attached, the microRNA either cuts out the section of messenger RNA that encodes the target protein, or it just sits on top of the messenger RNA, blocking ribosomes from translating the RNA into a protein. Either way, a certain protein that would otherwise have been made is instead suppressed. The outcome is the same as “turning off” the gene itself. 

Which protein does microRNA-141-3p block from being made? AU-rich RNA-binding factor 1 (AUF1). Usually, AUF1 is involved in the regulation of messenger RNA stability and in determining which proteins are made. In younger people, AUF1 actively suppresses the production of pro-inflammatory proteins, which, if left unchecked, might otherwise lead to chronic inflammation — a hallmark of aging. AUF1 also helps curb “cell senescence”, which is when cells become old and lose their ability to function normally. In particular, senescent cells stop multiplying but don’t die off as they usually would, instead spewing chemicals that trigger inflammation. So blocking microRNA-141-3p should, in theory, also help stave off cell senescence and the onset of chronic inflammation. 

Denser Bones, Stronger Muscles 

To test their theory, the researchers turned to “antagomirs”. These are tailor-made molecules engineered to block a particular microRNA. Although currently restricted to research, antagomirs may eventually be harnessed to treat a variety of human conditions. 

The scientists treated elderly mice, around 60 in human years, with the antagomir for three months, administering the molecule by injection twice a week. Afterward, they analyzed the spleen, muscles, and bones of the mice and compared them to a control group that did not receive the antagomir treatment. Under the microscope, the mice treated with the antagomir looked significantly more “youthful” than their counterparts: inflammation in the spleen and blood was reduced, their bones were denser and stronger, and they had noticeably more muscle fiber. 

Specifically, proteins in the blood that upregulate inflammation —tumor necrosis factor alpha (TNF-α), interleukin-1 beta (IL-1β), and interferon gamma (IFN-γ)— declined with antagomir treatment. In the spleen, treated mice had a higher proportion of M2 macrophages. These are immune cells that help suppress inflammation and repair tissue damage. M1 macrophages, in turn, are known to promote inflammation and were substantially higher in the untreated mice. Indeed, previous research has shown that M2 macrophages are integral to healthy human skeletal muscle. 

The authors note that, to their knowledge, this study is the first to show that blocking microRNA-141-3p can decrease age-related inflammation and curb muscle and bone decline with age. And they are already looking ahead to new questions and challenges: can microRNA-141-3p be administered for longer periods of time without adverse effects? What role, if any, do microRNAs play in cognitive decline? 

Takeaways

As always, it is important to note that this study was performed in mice, not humans; outcomes in animal models do not always accurately reflect human outcomes. Still, the research acts as a valuable “proof of principle” that targeting microRNA-141-3p can help keep at bay many of the changes considered to be hallmarks of the aging body. This includes chronic low-level inflammation, loss of muscle mass, and weakening of the bones. For now, antagomirs are restricted to research, but down the line, they might help us stay healthy into old age.

This article was originally published on Forbes and can be read online here.