In today's research materials, the authors report on the use of follistatin-like molecules to enhance bone density and increase muscle mass in mice. Myostatin and follistatin are well known to control muscle growth, and are consequently among the most promising targets for near future gene therapies. Either inhibition of myostatin, which can be achieved via antibody therapies in addition to gene therapies, or upregulation of follistatin can be used to deliver increased muscle growth in mammals. There are natural myostatin loss of function mutants in many species, including a few humans, and a range of heavily muscled engineered lineages in mice, dogs, and the like. There is robust evidence for this alteration to be essentially beneficial, and it does in fact modestly increase life span in mice in addition to the direct benefits relating to muscle mass.
While additional muscle growth at any age sounds quite desirable, the main reason for considering this sort of therapy is to slow or perhaps turn back to some degree the characteristic loss of muscle mass and strength that occurs with advancing age. This happens to everyone, and is given the name sarcopenia. While targeting myostatin or follistatin seems likely to be effective to some degree, and reliably effective if the animal data is any guide, it doesn't address the underlying causes. It is a compensatory approach only, and even the highly effective compensatory approaches eventually run into the wall of ever-increasing molecular damage that overflows the mechanisms of compensation.
The interesting aspect of the line of work supporting the research noted here, which apparently dates back quite a few years, is that follistatin is just one point in a spectrum of potential molecules that can influence bone density in addition to muscle mass. The myostatin / follistatin gene therapies of the near future may turn out to deliver follisatin-like molecules into tissues rather than follistatin itself, these molecules tailored to specific outcomes in their bone or muscle development.
Researchers have studied a new group of medication which could prove beneficial for the elderly and the chronically ill who suffer a loss of bone- and muscle mass. They have named the group of medicinal products IASPs, Inhibitors of the Activin-receptor Signaling Pathway. IASPs inhibit a signal pathway which is found in virtually all cells. The difference between the various medications in the group is that they inhibit different routes into the pathway. The researchers have shown that it is possible to achieve an effect on different tissues such as muscle tissue, bone tissue, or blood cells depending on the IASP they used.
"We found an increased muscle mass of 19 per cent in mice after just one week. At the same time as an effect on the muscle mass, we saw that the drugs also counteracted osteoporosis." However, there is an Achilles heel. The effect on the blood cells has presented the researchers with a challenge. Thus far the drugs in the group of medicinal products have stimulated the formation of red blood cells. "This isn't bad if we're dealing with someone suffering from anaemia, low muscle mass, and osteoporosis all at once, as is the case for some. But for the majority of patients with a normal blood per cent, this increases the risk of blood clots." The researchers have therefore been working on a solution. They have succeeded in creating a molecule in the IASP group which for the first time works on bones and muscles but does not affect the blood.
Inhibitors of the activin receptor signaling pathway (IASPs) have become candidate therapeutics for sarcopenia and bone remodeling disorders because of their ability to increase muscle and bone mass. However, IASPs utilizing activin type IIA and IIB receptors are also potent stimulators of erythropoiesis, a feature that may restrict their usage to anemic patients because of increased risk of venous thromboembolism. Based on the endogenous TGF-β superfamily antagonist follistatin (FST), a molecule in the IASP class, FSTΔHBS-mFc, was generated and tested in both ovariectomized and naive mice.
In ovariectomized mice, FSTΔHBS-mFc therapy dose-dependently increased cancellous bone mass up to 42% and improved bone microstructural indices. For the highest dosage of FSTΔHBS-mFc, the increase in cancellous bone mass was similar to that observed with parathyroid hormone therapy. The quadriceps femoris muscle mass dose-dependently increased up to 21% in ovariectomized mice. In both ovariectomized and naive mice, FSTΔHBS-mFc therapy did not influence red blood cell count or hematocrit or hemoglobin levels. If the results are reproduced, a human FSTΔHBS-mFc version could be applicable in patients with musculoskeletal conditions irrespective of hematocrit status.