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