By delivering the protein follistatin via gene therapy, researchers at Washington University in St. Louis were able to increase skeletal muscle mass, decrease fat, and reverse obesity-related arthritis in mice who developed osteoarthritis as a result of a high-fat diet.
They reported their results in the May 8, 2020, online issue of Science Advances.
“What we were really excited about is showing how important muscle is in arthritis,” senior author Farshid Guilak told BioWorld. “High muscle mass can burn off so many of the worst aspects of [a] high-fat diet.”
Guilak, who is a professor of orthopedic surgery at Washington University and director of research at Shriners Hospitals for Children - St. Louis, and his team had previously looked at the effects of exercise on osteoarthritis by giving the animals access to running wheels. Given such access, animals will spontaneously run “easily two to three miles a night,” Guilak said, which also improved their osteoarthritis.
By using gene therapy, the team was able to look at the specific effects of muscle tissue in the absence of exercise, which affects multiple physiological systems.
The team delivered an adeno-associated virus 9 (AAV9) vector containing the gene for follistatin, whose expression increases skeletal muscle formation.
The specific choice of follistatin, Guilak explained, was “mostly for safety – follistatin is basically the molecule that’s the inhibitor of myostatin, and myostatin is the protein that puts the brakes on muscle.”
Follistatin is not part of the regulatory mechanism for heart muscle, so its delivery would not be expected to lead to cardiac hypertrophy. And, indeed, the team showed that the animals did not suffer from cardiac hypertrophy. Instead, their cardiac function improved after follistatin treatment.
Animals treated with follistatin had approximately twice the muscle mass and strength as controls. Follistatin also promoted the conversion from energy-storing white fat to energy-burning brown fat, reduced the levels of proinflammatory adipokines, and decreased both joint damage and pain sensitivity in treated animals, even though they continued to be fed a diet that derived 60% of its calories from fat – “worse than any fast food diet you could get,” he said.
The treatment works both by decreasing systemic inflammation and by stabilizing joints.
Guilak said that despite the promising results, the target population for follistatin gene therapy is “probably not going to be someone who is overweight and has a joint injury, [where] the first thing that we would recommend to anyone is to lose weight and exercise.”
Instead, he pointed to untreatable wasting, both in muscular dystrophies and in sarcopenic obesity, a condition where muscles aren’t strong enough relative to body weight. Sarcopenic obesity, which is most likely to occur in elderly individuals with both decreased muscle mass and muscle strength, can be life-threatening.
Follistatin gene therapy is being tested in phase I/II trials for both Becker and Duchenne muscular dystrophy by Milo Biotechnology, and it has been tested in mouse models of facioscapulohumeral muscular dystrophy (FSHD).
At the upcoming annual meeting of the American Society for Gene and Cell Therapy, scientists from Immusoft Corp. will also present preclinical data on using nonvirally transformed B cells to deliver follistatin.
Follistatin may be useful in cancer treatment as well. A 2019 paper reported that inhibiting the protein activin-A with follistatin increased the antitumor effects of natural killer (NK) cells. Other researchers have shown that follistatin could increase the therapeutic index of platinum chemotherapy, also by inhibiting activin.
Osteoarthritis, which results from the breakdown of cartilage, is by far the most common form of arthritis, affecting nearly 30 million individuals in the US. Increasing follistatin levels could also potentially be useful in rheumatoid arthritis, though Guilak said that the disease process is “very different – rheumatoid arthritis is an autoimmune disease, so it’s very inflammatory.” The role of muscle in rheumatoid arthritis has been less studied than in osteoarthritis, but obesity is a risk factor here, as well.
The work also helps clarify the effects of high weight vs. low muscle mass, which often go together as part of a sedentary lifestyle.
The bottom line, Guilak said, is that “being overweight by itself is not that bad.” In his team’s previous experiments, animals who had access to treadmills ran several miles a day. Those mice “were much healthier” than sedentary controls, he said. “But they didn’t lose any weight at all.”
Excess weight appears to become a problem at extreme levels.
“If you are really overweight and obese, what happens is that your fat cells start to get so large that many of them just die,” Guilak said.
Problems start when debris from the dying cells signals the need for cleanup to the immune system, and macrophages that move into fat stay there, setting off low-grade but long-term inflammatory signaling that increases the risk of multiple diseases.