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Follistatin Gene Therapy Doubles Muscle Mass in Mice


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Posted 18 May 2020 - 07:42 PM


Follistatin is an inhibitor of myostatin. Blocking myostatin activity enhances muscle growth, with accompanying beneficial side-effects such as a loss of excess fat tissue. This is well proven. There are a good number of animal lineages (mice, dogs, cows, and so forth) resulting from natural or engineered myostatin loss of function mutations, and even a few well-muscled human individuals with similar mutations. A number of groups are at various stages in the development of therapies to either upregulate follistatin or inhibit myostatin. The latter is further along in the formal regulatory process: human trials have been conducted for myostatin antibody therapies. Meanwhile, first generation follistatin gene therapies, such as that pioneered by BioViva Science, are available at great expense through the medical tourism market, such as via Integrated Health Systems, with all too little data on their efficacy.

In a world in which gene therapies become cheap and reliable, which will happen over the next ten to twenty years, follistatin upregulation will likely be one of the more widely available enhancement therapies. Who doesn't want more muscle, less fat, and a better metabolism, and all of that lasting for longer into later life? Unfortunately, gene therapy platforms are at present not all that efficient when it comes to systemic delivery throughout the body, at least not without a great deal of optimization to the specific use case. It is true that targeting muscle can be more a matter of scores of relatively unoptimized intramuscular injections rather than some form of infusion, but in both cases the cost is presently prohibitive for most people, and results in humans are yet to be robustly quantified. Expectations on safety are at present influenced more by the large numbers of mammalian myostatin loss of function mutants than by clinical data.

All of this said, it remains the case that work continues in laboratories to produce well muscled mice via follistatin gene therapies. The research noted here is an example of the type, a study that is little different from those performed in mice more than a decade ago. A few new assessments are made, and are interesting in and of themselves. Nonetheless, the wheels of science turn slowly indeed.

Gene therapy in mice builds muscle, reduces fat

Building muscle mass and strength can take many months and be difficult in the face of joint pain from osteoarthritis, particularly for older people who are overweight. A new study in mice, however, suggests gene therapy one day may help those patients. The research shows that gene therapy helped build significant muscle mass quickly and reduced the severity of osteoarthritis in the mice, even though they didn't exercise more. The therapy also staved off obesity, even when the mice ate an extremely high-fat diet.

The research team gave 8-week-old mice a single injection each of a virus carrying a gene called follistatin. The gene works to block the activity of a protein in muscle that keeps muscle growth in check. This enabled the mice to gain significant muscle mass without exercising more than usual. Even without additional exercise, and while continuing to eat a high-fat diet, the muscle mass of these "super mice" more than doubled, and their strength nearly doubled, too. The mice also had less cartilage damage related to osteoarthritis, lower numbers of inflammatory cells and proteins in their joints, fewer metabolic problems, and healthier hearts and blood vessels than littermates that did not receive the gene therapy. The mice also were significantly less sensitive to pain.

One worry was that some of the muscle growth prompted by the gene therapy might turn out to be harmful. The heart, for example, is a muscle, and a condition called cardiac hypertrophy, in which the heart's walls thicken, is not a good thing. But in these mice, heart function actually improved, as did cardiovascular health in general. Longer-term studies will be needed to determine the safety of this type of gene therapy. But, if safe, the strategy could be particularly beneficial for patients with conditions such as muscular dystrophy that make it difficult to build new muscle.

Gene therapy for follistatin mitigates systemic metabolic inflammation and post-traumatic arthritis in high-fat diet-induced obesity

Obesity-associated inflammation and loss of muscle function play critical roles in the development of osteoarthritis (OA); thus, therapies that target muscle tissue may provide novel approaches to restoring metabolic and biomechanical dysfunction associated with obesity. Follistatin (FST), a protein that binds myostatin and activin, may have the potential to enhance muscle formation while inhibiting inflammation. Here, we hypothesized that adeno-associated virus 9 (AAV9) delivery of FST enhances muscle formation and mitigates metabolic inflammation and knee OA caused by a high-fat diet in mice. AAV-mediated FST delivery exhibited decreased obesity-induced inflammatory adipokines and cytokines systemically and in the joint synovial fluid. Regardless of diet, mice receiving FST gene therapy were protected from post-traumatic OA and bone remodeling induced by joint injury. Together, these findings suggest that FST gene therapy may provide a multifactorial therapeutic approach for injury-induced OA and metabolic inflammation in obesity.


View the full article at FightAging




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