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June 16, 2009

Myostatin Blockers Protect Against Obesity And Atherosclerosis: Along with Boosting Muscle



Myostatin inhibition genes and myostatin blocking effects are in about one person in one million. A child Liam Hoekstra has it and is shown climbing rope at the age of three. Champion body builder Flex Wheeler has the myostatin inhibited genes.

1. Knockout of myostatin, a growth factor that limits muscle growth, can decrease body fat and promote resistance against developing atherosclerosis, or "hardening" of the arteries, according to a new study conducted in mice.

Obesity increases the risk of atherosclerosis, which accounts for 75% of all cardiovascular events, such as heart attacks and strokes.

The mice with deleted myostatin gene had much less body fat and 30 percent lower fasting blood sugar and 80% lower fasting insulin levels, showing a reduction in obesity and a strong resistance to developing diabetes, the authors reported. They also had 50 percent lower low-density-lipoprotein ("bad") cholesterol and 30 to 60 percent lower levels of total cholesterol and triglycerides (fats in the blood), respectively. These results indicate protection against the development of atherosclerosis.






More research is needed to demonstrate the safety and effectiveness of myostatin inhibitors in humans, Bhasin said. However, he said that that this therapeutic strategy already is possible. Experimental drugs called myostatin blockers or inhibitors are being studied as potential treatments of muscle wasting disorders and limb injuries.

2. Myostatin inhibitors may improve recovery of wartime limb injuries.

"Myostatin also increases fibrosis and scarring within tissue so part of what you are doing is blocking that."

Bone and muscle healing typically go hand in hand. Muscle provides blood, growth factors and potentially stem cells for a healing callus. It's not yet known how well bones reciprocate. "If you can improve muscle healing, you can improve bone healing," Dr. Hamrick says. "Young people have a tremendous potential to heal that can be improved with better approaches to preventing infection and to healing soft tissue and bone in an integrated manner."

Researchers hope to move to clinical trials in two to three years, Dr. Hamrick says. "If we find the primary role of myostatin is very early in the healing process and see a big jump in expression early in a fracture callus, it may be that a single injection bolus immediately after injury is the best time for treatment rather than continued treatment over a period of time."


3. Earlier Myostatin drugs are possibly four times more effective than high doses of steroids in growing muscle.

4. University of Cincinnati Awarded $1.5 Million for ‘Muscle-Wasting Disease’ Study

Tom Thompson, PhD, an assistant professor in the department of molecular genetics, biochemistry and microbiology, University of Cincinnati, is studying myostatin, a protein that regulates muscle growth and is naturally found in animals. Antagonizing myostatin—stopping it from working—through protein inhibitors would stimulate muscle growth.

Thompson hopes his research will lead to the rational design of myostatin inhibitors that could be used therapeutically for muscle-wasting diseases.

5. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease.

Center for Gene Therapy, Research Institute at Nationwide Children's Hospital, 700 Children's Drive, Columbus, Ohio 43205 USA.

In most cases, pharmacologic strategies to treat genetic muscle disorders and certain acquired disorders, such as sporadic inclusion body myositis, have produced modest clinical benefits. In these conditions, inhibition of the myostatin pathway represents an alternative strategy to improve functional outcomes. Preclinical data that support this approach clearly demonstrate the potential for blocking the myostatin pathway. Follistatin has emerged as a powerful antagonist of myostatin that can increase muscle mass and strength. Follistatin was first isolated from the ovary and is known to suppress follicle-stimulating hormone. This raises concerns for potential adverse effects on the hypothalamic-pituitary-gonadal axis and possible reproductive capabilities. In this review we demonstrate a strategy to bypass off-target effects using an alternatively spliced cDNA of follistatin (FS344) delivered by adeno-associated virus (AAV) to muscle. The transgene product is a peptide of 315 amino acids that is secreted from the muscle and circulates in the serum, thus avoiding cell-surface binding sites. Using this approach our translational studies show increased muscle size and strength in species ranging from mice to monkeys. Adverse effects are avoided, and no organ system pathology or change in reproductive capabilities has been seen. These findings provide the impetus to move toward gene therapy clinical trials with delivery of AAV-FS344 to increase size and function of muscle in patients with neuromuscular disease.


PMID: 19208403

6. AAV-dependent targeting of myostatin function: Follistatin strikes back at muscular dystrophy

Haidet et al. provide new and valuable data about a novel and potentially clinically relevant strategy for muscle regeneration in DMD. A number of issues, however, remain to be addressed to move their results from the bench to the bedside.


7. Long-term enhancement of skeletal muscle mass and strength by single gene administration of myostatin inhibitors

Amanda M. Haidet et al

These results suggest that inhibition of myostatin by FS-344, delivered by a single AAV1 injection can enhance muscle size and strength and is well tolerated for >2-years. The results of FS344 may offer a more powerful strategy than others targeting solely myostatin because of additive effects, such as follistatin's involvement in multiple signaling pathways, and the recent finding demonstrating a reduction in inflammation in a model of endotoxemia. The striking ability of FS to provide gross and functional long-term improvement to dystrophic muscles in aged animals warrants its consideration for clinical development to treat musculoskeletal diseases, including older DMD patients.


FURTHER READING

Links related to follistatin trials


Video of Liam Hoekstra, 3, who has myostatin blocking genes

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