Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle

Abstract

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 fusioncompetent 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 (5 *

PGRMC1 effects on metabolism, genomic mutation and CpG methylation imply crucial roles in animal biology and disease

“…The NNMT pathway has been linked to lifespan and aging [66][67][68][69], to sirtuin protein stabilization in positive a feedback loop to the pathway in Fig. 6b involved in energy regulation and obesity [52,70,71] and to epigenetics in cancer and stem cell status [52,[72][73][74] (reviewed by [75]).…”

PGRMC1 phosphorylation and cell plasticity 2: genomic integrity and CpG methylation

“…The NNMT pathway has been linked to lifespan and aging (Calvani et al, 2014;Neelakantan et al, 2019;Schmeisser et al, 2013;Schmeisser and Parker, 2018), to sirtuin protein stabilization in positive a feedback loop to the pathway in Figure 6C involved in energy regulation and obesity (Hong et al, 2015;Kraus et al, 2014;Strom et al, 2018), and to epigenetics in cancer and stem cell status (Jung et al, 2017;Sperber et al, 2015;Ulanovskaya et al, 2013;Xie et al, 2014) (reviewed by (Pissios, 2017)). We show that PGRMC1 Y180 modulates this system.…”

Coronavirus infection and PARP expression dysregulate the NAD Metabolome: an actionable component of innate immunity

“…Notably, in mouse models of damaged brain and heart, upregulation of NMRK gene expression is associated with therapeutic efficacy of NR (31)(32). Additionally, the ferret data show strongly depressed NNMT expression-by decreasing NAM methylation, this gene expression change could promote NAM salvage (33) and the efficiency of NAD-boosting by NR or NAMPT activators (24), representing a homeostatic attempt of virally infected cells to maintain their NAD metabolome (34).…”