P311 knockout increased force production by 19% in injured muscle from aged mice
P311 knockout increased force production by 19% in injured muscle from aged mice
On August 22, the authors reported an experiment in 24-month-old mice in an npj Aging article. They knocked out P311 throughout the body and chemically injured the tibialis anterior muscle. At 28 days after injury, this muscle produced 19% more force than the same muscle in age-matched mice with intact P311.
In aged animals, injured muscle often heals with excess collagen. This collagen forms fibrotic connective tissue and prevents muscle fibers from fully recovering their function. The authors selected P311 because previous studies had linked the protein encoded by this gene to the production of TGF-β, a signaling molecule that promotes the formation of fibrotic tissue. After injury, P311 and TGF-β levels increased more strongly in aged muscle than in young muscle.
The authors first examined the tissue component of this pathway. At 14 days after injury, muscle from mice without P311 contained less collagen and showed lower activity of genes associated with fibrosis. At 28 days, the mean cross-sectional area of regenerated fibers was 25% larger. The same tibialis anterior muscle also produced 19% more force.
The team then investigated which cells express P311. A reanalysis of published single-cell data showed that P311 is particularly active in fibro-adipogenic progenitors (FAP), connective tissue cells in muscle that contribute to its repair. During fibrosis, FAP deposit collagen around muscle fibers. In laboratory culture, FAP from aged mice with intact P311 deposited approximately three times as much collagen as cells from young mice. In aged mice with P311 knockout, collagen deposition fell to a level comparable to that observed in young mice.
In this model, global P311 knockout reduced age-related fibrosis after injury. The regenerated fibers were larger, and the muscle produced more force. The FAP findings provide a likely cellular explanation for this result.