Muscles healing after injury, during normal aging or in response to diseases like Duchenne muscular dystrophy often develop excess connective tissue that inhibits the ability of the fibers to contract or relax normally. Now Stanford researchers, including neurologist Thomas Rando, MD, PhD, have come up with a way in mice to mitigate this condition, known as fibrosis, or scarring. They did so by studying how muscle stem cells respond to such threats.
From our release:
The researchers discovered that stem cells embedded in muscle fibers do some fancy gene-expression footwork in order to respond appropriately to injury, disease or aging. In particular, the cells toggle between producing a full-length, active version of a protein that responds to external signals to divide and a shorter, inactive version of the same protein that attenuates the growth signal and prevents an overly enthusiastic response that can lead to scarring or fibrosis.
Rando, who directs Stanford’s Glenn Center for the Biology of Aging, and his colleagues found a way to modulate the stem cells’ production of the inactive, inhibitory form of the PDGFR alpha protein, which reduces scarring. As I explained in the release:
Mueller, Rando and their colleagues used a type of small molecule called a vivo-morpholino that can bind and block access to small sections of messenger RNA to artificially increase or decrease expression of the inhibitory version of the PDGFR alpha protein. They found that increasing the amounts of the inhibitory version allowed both young and old mice to heal from injury with less fibrosis and scarring. Conversely, decreasing the amount increased the severity of fibrosis.
‘We’d like to test this approach in a mouse model of muscular dystrophy next,’ said Rando. ‘Interestingly, the vivo-morpholino we used is similar to a small oligonucleotide therapy currently being tested in clinical trials to stimulate the production of proteins missing in patients with Duchenne muscular dystrophy. Perhaps we could also use this approach to reduce fibrosis in this disease.’
The work was published today in Nature.
Previously: “Home away from home:” Artificial muscle fibers keep lab-grown stem cells happy, Tick tock goes the clock–Is aging the biggest illness of all? and Stem cells implicated in Duchenne muscular dystrophy
Photo of human muscle fibers by NIH Image Gallery