Myostatin Insufficiency Produces 15% Life Extension in Mice

Targeting myostatin and related biochemistry is well demonstrated to increase muscle mass and strength in mammals such as laboratory mice. There are even rare natural mutants, including a few cows and humans, who lack normal myostatin and are as a result exceptionally strong in comparison to their peers. Here researchers show that loss of myostatin mutations in mice produce extended life spans, but too much suppression of myostatin may remove that benefit due to the cardiac issues that can accompany an overly large heart:

The molecular mechanisms behind aging-related declines in muscle function are not well understood, but the growth factor myostatin (MSTN) appears to play an important role in this process. Additionally, epidemiological studies have identified a positive correlation between skeletal muscle mass and longevity. Given the role of myostatin in regulating muscle size, and the correlation between muscle mass and longevity, we tested the hypotheses that the deficiency of myostatin would protect oldest-old mice (28-30 months old) from an aging-related loss in muscle size and contractility, and would extend the maximum lifespan of mice. We found that MSTN+/− and MSTN−/− mice were protected from aging-related declines in muscle mass and contractility. While no differences were detected between MSTN+/+ and MSTN−/− mice, MSTN+/− mice had an approximately 15% increase in maximal lifespan. These results suggest that targeting myostatin may protect against aging-related changes in skeletal muscle and contribute to enhanced longevity.

The mechanism behind the increased longevity of MSTN+/− mice is not known, but inhibition of myostatin can reduce systemic inflammatory proteins and body fat. Given the increase in relative heart mass, the contribution of aging-associated cardiomegaly to mortality and that inhibition of myostatin can increase heart mass, it is possible that positive effects of increased skeletal muscle mass on the longevity of MSTN−/− mice was offset by cardiac pathologies. Most genetic models of enhanced longevity in mice have identified an inverse relationship between body mass and longevity, which has lead to the observation that 'big mice die young'. However, the results from the current study support the epidemiological observations in humans that when it comes to skeletal muscle mass and longevity, bigger may be better.

Link: http://onlinelibrary.wiley.com/enhanced/doi/10.1111/acel.12339/

Comments

This appears to be the usual case of partially making up for poor animal husbandry, rather than a true extension of the normal, healthy lifespan. Per their survivorship data, their WT controls have mean and maximal survivorships of 782 and 1037 days, vs. 858 and 1201 days for their -/+ mice; for comparison, the numbers for normal, healthy, nonobese, non-genetically-messed-up, non-toxin-fed mice should be ≈900 and ≈1100 d, respectively. That does still leave at least a suggestion of an effect on max LS, but I have seen Weindruch/Walford control groups with max LS this long. IAC, the main effect is against short-living controls.

It's not the genetics -- "The background strain of the mice was C57BL/6" (Supplementary Data S1 Experimental procedures) -- but I'd say there's good reason to think it's the classic "fat rats" problem: all they say about food intake is "standard Lab Diet 5001 chow (Purina Lab Diet, St. Louis, MO) ad libidum", which absent additional precaution means the animals spent all day snacking their way into metabolic morbidity. And the authors say (evidently not thinking of this confounder):

The mechanism behind the increased longevity of MSTN+/− mice is not known, but inhibition of myostatin can reduce systemic inflammatory proteins and body fat (Gumucio & Mendias, 2013 [PMID: 22815045])".

Quickly skimming & "Find"-ing through the latter, I don't actually see where this is documented, but it's consistent with PMIDs 21197386, 20877574, and 19208906, and also with studies reviewed in the last of these citations:

Knockout of the Mstn gene (Mstn [for myostatin]) from agouti lethal yellow (Ay) and obese (Lepob/ob) mice [two genetic models of extreme obesity, the latter being knockout of the leptin receptor -MR] improves glucose tolerance, increases muscle mass, and decreases adiposity (6). Obesity-prone Ay and Lepob/ob Mstn null mice have body sizes roughly equal to those of their littermate controls due to a diametrical change in muscle and fat characterized by fewer adipocytes that are reduced in size and hyperplasia and hypertrophy of individual muscle fibers. In addition, Mstn knockout mice exhibit an ability to fend off age-related expansion of adipose tissue mass by keeping their fat cells small, unlike wild types, which have enlarged adipocytes contributing to increasing adiposity with age. Evidently, knockout mice experience continued protection against obesity over the later part of their lifespan as they age compared with wild-type mice, yet they have similar total and resting metabolic rates.

Of course, this is what you'd expect from a mutation that drives fuel into muscle building. So I'm going to guess that the mutation kept their -/+ animals at normal leanness, leading to normal LS, while their controls became obese and metabolically morbid, and accordingly short-lived.

Posted by: Michael at March 27th, 2015 11:28 AM

@Michael:- Thank you for the analysis. Unfortunately "the animals spent all day snacking their way into metabolic morbidity" aptly describes a large proportion of the human population as well. If myostatin knockout/inhibition can mitigate the detrimental effects of such, that's still a suggestion of its utility.

There's also the question whether age-related sarcopenia would be expected to have a measurable negative effect on lifespan or only on quality of life.

Posted by: José at March 27th, 2015 12:53 PM

José wrote: Unfortunately "the animals spent all day snacking their way into metabolic morbidity" aptly describes a large proportion of the human population as well. If myostatin knockout/inhibition can mitigate the detrimental effects of such, that's still a suggestion of its utility.

... as a treatment for Type II diabetes and metabolic syndrome, perhaps. But that's quite a different thing from a genuine extension of normal, healthy lifespan.

José wroteThere's also the question whether age-related sarcopenia would be expected to have a measurable negative effect on lifespan or only on quality of life.

I don't think there's really a question there. However:

(a) if you were going to inhibit myostatin as a treatment for sarcopenia, you'd presumably do it for a short period relatively late in the LS: this putative 15% increase in LS comes from a lifelong haploinsufficiency; and

(b) inhibiting myostatin is a dubious strategy against sarcopenia in any case. Even in young, healthy animals, inhibition of myostatin leads to bigger but proportionately weaker muscles, apparently in part because it causes myocyte hypertrophy but fails to recruit myoblasts, leading to muscles that can't be fully recruited to generate force. When you consider doing this to biologically aged people with sarcopenia or its beginnings, you have to remember that there's a lot of things wrong with old muscle tissue beyond mere atrophy, including degeneration of neuromuscular junctions, mitochondrial impairments, infiltration and replacement of muscle tissue with adipose and collagen, etc. As a result, old muscle, like muscle grown through myostatin inhibition, is disproportionately weak to its mass compared to young muscle. Just adding intrinsically dysfunctional mass onto a degenerating foundation is not a good solution.

Posted by: Michael at March 27th, 2015 4:44 PM

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