A Small Molecule NNMT Inhibitor Puts Aged Stem Cells Back to Work to Improve Muscle Regeneration in Old Mice

In old tissues, stem cell activity is much reduced relative to youthful activity. This is thought to be the most important contribution to loss of muscle mass and strength with age, leading to the condition known as sarcopenia. It also diminished the ability to regenerate after muscle injury. Numerous studies in the regenerative medicine community have demonstrated that while this loss of stem cell function may be a defense against cancer, reducing the activity of cells that may bear potentially dangerous molecular damage, there appears to be a fair amount of room to push the balance towards greater activity without large increases in cancer risk. In mice, anyway.

Researchers here demonstrate a novel way of increasing muscle stem cell activity, to add to a number of others that have been shown to work to some degree in animal studies. The mechanism is arguably somewhat related to work on ways to increase levels of NAD+ so as to enhance mitochondrial activity in old tissues. Here the effect size on muscle regeneration in mice is certainly large enough to be interesting. We'll no doubt see what it does in humans fairly soon, even ahead of human trials, as the self-experimentation community decides to try this out. One would hope they would go about it more carefully than is usually the case in body building circles.

Aging is accompanied by progressive declines in skeletal muscle mass and strength and impaired regenerative capacity, predisposing older adults to debilitating age-related muscle deteriorations and severe morbidity. Muscle stem cells (muSCs) that proliferate, differentiate to fusion-competent myoblasts, and facilitate muscle regeneration are increasingly dysfunctional upon aging, impairing muscle recovery after injury. While regulators of muSC activity can offer novel therapeutics to improve recovery and reduce morbidity among aged adults, there are no known muSC regenerative small molecule therapeutics.

We recently developed small molecule inhibitors of nicotinamide N-methyltransferase (NNMT), an enzyme overexpressed with aging in skeletal muscles and linked to impairment of the NAD+ salvage pathway, dysregulated sirtuin 1 activity, and increased muSC senescence. We hypothesized that NNMT inhibitor (NNMTi) treatment will rescue age-related deficits in muSC activity to promote superior regeneration post-injury in aging muscle.

24-month old mice were treated with saline (control), and low and high dose NNMTi for 1-week post-injury, or control and high dose NNMTi for 3-weeks post-injury. In vivo contractile function measurements were conducted on the injured tibialis anterior (TA) muscle and tissues collected for ex-vivo analyses, including myofiber cross-sectional area (CSA) measurements to assess muscle recovery. Results revealed that muscle stem cell proliferation and subsequent fusion were elevated in NNMTi-treated mice, supporting nearly 2-fold greater CSA and shifts in fiber size distribution to greater proportions of larger sized myofibers and fewer smaller sized fibers in NNMTi-treated mice compared to controls.

Prolonged NNMTi treatment post-injury further augmented myofiber regeneration evinced by increasingly larger fiber CSA. Importantly, improved muSC activity translated not only to larger myofibers after injury but also to greater contractile function, with the peak torque of the TA increased by ∼70% in NNMTi-treated mice compared to controls. Taken together, these results provide the first clear evidence that NNMT inhibitors constitute a viable pharmacological approach to enhance aged muscle regeneration by rescuing muSC function.

Link: https://doi.org/10.1016/j.bcp.2019.02.008

Comments

@Reason: In your introductory comments you make reference to higher levels of NAD+ increasing mitochondrial activity in old tissues, but perhaps more importantly, added NAD+ increases DNA repair and the reprogramming and activation of adult stem cells in old tissues. With age, adult stem cell activity is much reduced, so that NAD+ is a second way of promoting muscle cell (as well as other cell types) regeneration other than using the NNMT inhibitor.

Posted by: Biotechy Marcks at February 19th, 2019 6:45 AM

>...Prolonged NNMTi treatment post-injury further augmented myofiber regeneration evinced by increasingly larger fiber CSA...

That alone could be valuable if it works in humans. Could be used for emailed immune repair and reduced recovery period after surgery...

Posted by: Cuberat at February 19th, 2019 8:10 AM

Off-Topic: Does anyone else find the general reaction to the daily obituaries a bizarre form of "Normalcy Bias"? Today it is fashion icon Karl Lagerfeld, over the weekend it was pollster and political icon Pat Cadell. Nowhere in the commentary around these obits does sadness turn to outrage and the kind of "never again" commitment that technology advance enables. I can think of a large number of important people who will likely die of the consequences of aging in the next 11 year who will not yet be 90 in 2030. I sincerely hope 2019 will be the year Americans become outraged by death.

Posted by: Tom Schaefer at February 19th, 2019 9:15 AM

@Tom Schaefer

Never, because everyone thinks death is natural therefore no need to do anything against it.

Posted by: Dokuganryu at February 19th, 2019 10:00 AM

@Tom Schaefer: You make a great point. And these days it's just tribute after tribute on Twitter to the late person. It should be an outrage and uproar on the scale of racism or sexism. Our society is very strange at the moment...

Posted by: Steven B at February 19th, 2019 10:04 AM

Here is a great reference on the mitochondrial and stem cell enhancement resulting from NAD+ supplementation in Mice. Zang, et al, 2016 NAD repletion improves mitochondrial and stem cell function and enhances life span in mice.

Posted by: Biotechy Marcks at February 19th, 2019 11:27 AM

Apparently it is easy and satisfying to laud someone AFTER their death? Means the person doing the lauding doesn't need to do more...and it makes them feel good? Win...win?

I like to read the obits...to see what age they died at and from what...if accurate. The bonus is that "it ain't me"....so far. I pity those that die younger than myself...and am amazed at those that made it into their 90s.

Is there any outrage? Not on my part...I've got all I can do keep my own boat in trim. There are some things I can do that might postpone aging...I need to tend my own garden...that is do what is needed...like exercise.

Socially...the US has probably gone from just neurotic to near psychotic?

I remember a "quote" from some one who made it to 90....he mentioned that he had avoided politics quite a while before then. Outrage will make you sick?

Posted by: bob at February 27th, 2019 5:32 AM

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