As we age, the body’s ability to bounce back from muscle injuries fades fast – but scientists have now pinpointed a surprising type of cell that helps to direct repairs like a supervisor on a building site. By watching how these contractor cells coordinate clean-up and reconstruction, researchers uncovered a new lead: a hidden link between tissue recovery and chronic inflammation that could shape future treatments.
A muscle injury such as a strain barely breaks a teen’s stride but can be absolutely devastating for older adults. “If it does not repair properly, a muscle injury affecting an older adult can lead to a very drastic reduction of muscle mass in just a few weeks,” says Yonglun Luo, a professor studying regenerative medicine at Aarhus University.
That is because the ability of our muscles to regenerate – which is near-miraculous in youth – somehow dampens as we age. Researchers hoping to understand why extracted tiny pieces of injured muscles and learned how a cellular contractor calls the shots as muscle is rebuilt after an injury.
The findings provide a promising target for future treatment – including a tantalising potential link to chronic inflammation conditions, says Luo, who co-authored an article detailing the findings in Nature Communications. “Hopefully, understanding these cells will enable us to develop better treatments to help with muscle regeneration and preserve muscle mass” among older adults, he says.
Why muscle injuries hit harder with age
The skeletal muscle system is the largest organ in your body. Not only do they enable you to breathe and maintain body temperature but skeletal muscles are responsible for voluntary movements, “the ones that enable us to interact with the environment around us,” explains co-author Jean Farup, associate professor of biomedicine at Aarhus University.
“If you injure the cardiac tissue – the heart – you are in trouble,” says Farup, who researches how muscles change with age. “But due to the unique presence of stem cells, skeletal muscles can sustain an injury and then recover, sustain an injury and then recover, over and over again,” he says.
Muscle injuries run the gamut from the mundane (such as soreness after spending hours tending the garden) to the catastrophic (such as a total muscle tear from a car accident). To better understand why older people struggle to rebound from muscle injuries great and small, Farup and Luo needed to manufacture a standard muscle injury they could recreate among multiple people.
Three brave participants between 55 and 80 years old volunteered to purposefully injure themselves – under controlled circumstances – in the laboratory.
Muscles are prone to injury when they receive commands to contract while lengthening at the same time. “This is similar to when you walk downhill on a mountain,” Farup says. To create an express injury, the researchers asked the participants to try to extend their leg as a lever pushed it back down. “While they do that, the subjects use remote control to stimulate a muscle in their lower thigh with an electrical current,” producing a strong muscle contraction, Farup says.
Each participant did this 200 times.
“The combination of these lengthening contractions and the electric stimulation produces a fairly large muscle injury,” Farup says. He figures that this is about as much damage as you can do to a human ethically. “But we can do this knowing that the participants will be able to recover” after about two weeks of soreness.
The researchers used a thick bore needle to extract muscle biopsies before the injury and at several time points during recovery – two, eight and 30 days later.
Inducing injury to trace muscle repair
The authors say that studies on muscle regeneration typically rely on cross-sections of muscle tissue: researchers peer through microscopes to eyeball what cell types were involved and use protein analysis to try to determine their role in the healing process. But a technique called spatial transcriptomics enabled the team to go beyond what is visible to the eye.
A special device called a Visium spatial platform can intercept messenger RNA (mRNA) – cellular messages that reveal which sections of a cell’s DNA or genes are currently in use – and remember where in a tissue sample the RNA came from. The result is a map of the muscle tissue – which areas are still damaged and which areas are in the process of regeneration – complete with clues to what individual cells were doing. Then, comparing the samples collected days and weeks into the participants’ recovery “enables us to trace how gene expression changes during muscle injury and regeneration,” Luo explains.
Very close to areas of injury, the researchers found cells called fibro-adipogenic progenitors (FAP cells). They are adaptable cells that can become either connective tissue cells called fibroblasts or fat-storage cells called adipocytes based on need.
Previous studies in mice have suggested that FAP cells could act as cellular contractors, seemingly coordinating with stem cells and calling in immune cells to work as a demolition crew. “One of the first things you need to do in muscle regeneration is remove the damaged cells to make room for new cells to grow,” Farup explains. “We need certain cells from the immune system to come into the area of injury” and to tear down and dispose of these spent cells.
But previous researchers had been unable to find a smoking gun of communication between the FAP cells and the immune demolition crew.
The spatial transcriptomics revealed something “surprising,” Farup says. During recovery from the injury, FAP cells were producing a molecule called complement factor 3, a signal molecule used to produce an inflammation and immune response. “We did not anticipate that,” he says. “The dogma is that complement 3 is mainly produced in the liver and then released to the circulation, where it is involved in combatting various types of infection.” In this case, it seems the FAP cells are secreting complement 3 to summon macrophages – white blood cells that gobble up invading pathogens or dead cells.
But the FAP’s job was not over once the immune cells arrived. Based on the RNA they transcribed, they seemed to be “building the matrix scaffold for the new muscle to grow in”, Luo says. When that task is complete, the FAP cells seem to go dormant within the muscle until they are activated by the next injury, he explains.
Zooming in on the body’s repair signals
The team’s findings further solidify the FAP cells as a key player in muscle regeneration – working as a kind of carpenter-contractor that both coordinates the work of other cells and takes a more hands-on role in building scaffolding for the new muscle.
Instructions from FAP cells are essential for muscle regeneration. But if those FAP cells lose track of the goal, the consequences may be dire. Scientists knew that dysfunction of FAP cells might contribute to muscle wasting such as that seen in muscular dystrophy or type 2 diabetes – it could be that overeager cellular contractors are calling in too many demolition crews, which end up attacking healthy muscle.
Learning that FAP cells secrete the inflammation-activating complement factor 3 opens a new slate of questions, the researchers say. FAP cells are not just present in skeletal muscle – “they are in the liver, the heart and the kidney – most places within the body,” Farup says. Overactive FAP cells could “actually be involved in establishing chronic inflammation,” a suite of conditions that doctors have found challenging to treat because of their mysterious origins.
More studies will be needed to determine “what complications cause FAP cells to turn from a healthy part of muscle regeneration into something that might cause disease,” Luo says.
