The Prospects for Myostatin Therapies to Reverse Age-Related Loss of Muscle Mass and Strength
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Myostatin is a protein involved in regulating muscle growth in mammals. Occasionally natural mutants are born with a dysfunctional myostatin gene, and these individuals enjoy the wide-ranging benefits resulting from considerable additional muscle mass and less fat tissue throughout life, resulting in a lower incidence of a range of age-related conditions. There are even a few human myostatin mutants at the present time.

Studies in mice suggest that a number of ways to manipulate the activity of myostatin are comparatively safe, producing benefits with no significant side-effects. Conversely there are other methodologies that might be acceptable in a less risk-averse era, but which would never be developed into treatments or enhancement technologies when better options are available. They have shown unpleasant or unpredictable side-effects, and efforts to further their implementation have been dropped.

Why is all this relevant? Because we lose muscle mass and strength steadily with age, a condition known as sarcopenia, and the frailty that this produces speeds the downward spiral by making it ever harder to maintain a physically active lifestyle. Insofar as sarcopenia results from a chain of consequences that works out from the fundamental cellular and molecular damage that causes aging, a working package of rejuvenation treatments after the SENS model would both prevent and reverse this loss of muscle. But a patch treatment based on myostatin inhibition is a very much closer prospect, something that has already been accomplished in numerous ways in mice in recent years. Such a treatment wouldn't do anything about the underlying damage of aging, and thus would probably do little to extend life span, but it would greatly ameliorate one narrow outcome of aging in later life.

It is worth noting that sarcopenia is not yet recognized as a disease by FDA regulators despite years of engagement by the scientific community, millions of dollars in lobbying, and so on. Thus no-one can develop a commercial treatment for sarcopenia in the US, and this negatively impacts the ability to raise funds all the way back down the research and development chain. It's the same old story of costs imposed and progress held back.

Here is a very readable and informative short open access review paper on myostatin, sarcopenia, and the prospects for building a treatment:

Myostatin and Sarcopenia: Opportunities and Challenges - A Mini-Review

Since its discovery, multiple strategies to disrupt myostatin activity have been developed, including neutralizing antibodies, propeptides, soluble ActRIIB receptors, and interacting proteins (GASP-1, follistatin and FLRG). Although alterations in myostatin expression and activity in the context of aging are incompletely understood, several of its characteristics make it a unique and desirable therapeutic target for sarcopenia.

First, postnatal inhibition of myostatin unequivocally increases skeletal muscle mass in adult and older mammals. Specifically, we have observed that weekly injections of a neutralizing antibody to myostatin for 4 weeks significantly increases the relative weights of individual muscles by up to 17% in aged mice and improved indices of muscle performance and whole-body metabolism.

Second, the effects of targeted inhibition of myostatin are highly specific to skeletal muscle. Despite profound increases in skeletal muscle in the various species in which myostatin has been mutated, the masses of other organs and prevalence of cancer appear largely unaffected. In fact, several lines of evidence suggest that disruption of myostatin signaling may positively influence age-associated changes in other tissues - either directly or indirectly. Aged myostatin null mice exhibit increased bone mineral density and improved ejection fraction compared to wild-type mice. Moreover, mice in which the myostatin gene has been mutated or deleted are resistant to diet-induced obesity, dyslipidemia, atherogenesis, hepatic steatosis, and macrophage infiltration/activation in adipose tissue and skeletal muscle.

It is critically important to note that all strategies to inhibit myostatin are not created equal. Neutralizing antibodies and propeptides are designed to specifically target myostatin, but other approaches are less discerning. For example, there is significant enthusiasm regarding the myostatin interacting protein, follistatin, as an anabolic intervention. This has partly resulted from the finding that transgenic muscle-specific overexpression of follistatin caused a further doubling, or in sum, a quadrupling of muscle mass in the double-muscled myostatin null mouse. This suggests follistatin drives skeletal muscle growth in part through a mechanism other than inhibiting myostatin.

However, if not confined to skeletal muscle, pharmacological administration of follistatin would modulate the activity of numerous molecules other than myostatin [and] jeopardize pituitary and gonadal function. Similarly, pharmacological administration of soluble ActRIIB offers more horsepower with regard to muscle growth than more targeted means to inhibit myostatin but at the cost of less specificity and greater risk.

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