How to boost muscle regeneration and rebuild tissue

New research from the Salk Institute spotlights molecular changes in underlying age-related muscle loss and signposts potential Yamanaka factor therapy.

A research team at the Salk Institute in La Jolla, California has identified a stem cell-related muscle regeneration process and discovered that Yamanaka factors could lead the way to a therapy for repairing muscles after injury or protecting against frailty by rebuilding the muscle mass that is lost as we age.

Longevity.Technology: Losing muscle mass is part of aging; frail older people have lower muscle density and muscle mass, and this loss of muscle mass, not only contributes to disability in older people, but affects their ability to live independently and healthily. Researchers at the Salk Institute hope to counter this loss by accelerating the regeneration of muscle tissue. Understanding the underlying mechanisms related to muscle regeneration and growth and could mean a treatment in the future that could trigger an effective regeneration of tissue in aging adults.

In a study published in Nature Communications, the Salk team demonstrated that by using Yamanaka factors (compounds usually used in stem-cell research), they could increase the regeneration of muscle cells in mice by activating the precursors of muscle cells, called myogenic progenitors.

“Loss of these progenitors has been connected to age-related muscle degeneration,” says Salk Professor Juan Carlos Izpisua Belmonte, the paper’s senior author. “Our study uncovers specific factors that are able to accelerate muscle regeneration, as well as revealing the mechanism by which this occurred [1].”

The Yamanaka factors (Oct3/4, Sox2, Klf4, c-Myc) are a group of protein transcription factors that control how DNA is copied for translation into other proteins and that play a vital role in the creation of induced pluripotent stem cells – cells that have the ability to become any cell in the body.

“Our laboratory previously showed that these factors can rejuvenate cells and promote tissue regeneration in live animals,” says Chao Wang, first author of the study. “But how this happens was not previously known [1].”

Salk Institute
Induction of Yamanaka factors (OKSM) in muscle fibers increases the number of myogenic progenitors. Top, control; bottom, treatment. Red-pink color is Pax7, a muscle stem-cell marker. Blue indicates muscle nuclei. Credit: Salk Institute

The regeneration of muscle tissue is controlled by muscle stem cells, also called satellite cells. These satellite cells sit in a niche between a layer of connective tissue (basal lamina) and the muscle fibres (myofibres). The Salk team used two different mouse models to pinpoint the changes – whether muscle stem-cell-specific or niche-specific – that occurred following the addition of Yamanaka factors. In order to study the effects of the factors independent of the age of the subject, the team focused on younger mice.

In the myofiber-specific model, the researchers found that adding the Yamanaka factors accelerated muscle regeneration in mice; the factors achieved this by reducing the levels of a protein called Wnt4 in the niche and this in turn activated the satellite cells. However, in the satellite-cell-specific model, Yamanaka factors did not activate satellite cells, nor did they improve muscle regeneration; the research team hypothesised, therefore, that Wnt4 plays a vital role in muscle regeneration [2].

Professor Izpisua Belmonte feels the results of the study might eventually lead to new treatments by targeting Wnt4.

“Our laboratory has recently developed novel gene-editing technologies that could be used to accelerate muscle recovery after injury and improve muscle function,” he says. “We could potentially use this technology to either directly reduce Wnt4 levels in skeletal muscle or to block the communication between Wnt4 and muscle stem cells [1].”

As well as looking at muscle regeneration, the Salk team are investigating alternative ways of cell rejuvenation, including using mRNA and genetic engineering. They hope that the research could lead to new approaches that could, in the future, trigger tissue and organ regeneration.


Image credits: Shawn Kashou / Shutterstock and the Salk Institute