Редактирование: NNMT

Nicotinamide N-methyltransferase (EC 2.1.1.1)

==Publications==

{{medline-entry
|title=Small molecule nicotinamide N-methyltransferase inhibitor activates senescent muscle stem cells and improves regenerative capacity of aged skeletal muscle.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30753815
|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 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 ([[NNMT]]i) 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 [[NNMT]]i (5 and 10 mg/kg) for 1-week post-injury, or control and high dose [[NNMT]]i for 3-weeks post-injury. All mice underwent an acute muscle injury (barium chloride injection) locally to the tibialis anterior (TA) muscle, and received 5-ethynyl-2'-deoxyuridine systemically to analyze muSC activity. In vivo contractile function measurements were conducted on the injured 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 [[NNMT]]i-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 [[NNMT]]i-treated mice compared to controls. Prolonged [[NNMT]]i 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 [[NNMT]]i-treated mice compared to controls. Similar results were recapitulated in vitro with C2C12 myoblasts, where [[NNMT]]i treatment promoted and enhanced myoblast differentiation with supporting changes in the cellular NAD /NADH redox states. 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, supporting the development of [[NNMT]]i as novel mechanism-of-action therapeutic to improve skeletal muscle regenerative capacity and functional recovery after musculoskeletal injury in older adults.
|mesh-terms=* Aging
* Animals
* Cell Line
* Gene Expression Regulation
* Male
* Mice
* Muscle Contraction
* Muscle, Skeletal
* Myoblasts
* Nicotinamide N-Methyltransferase
* Random Allocation
|keywords=* Aged muscle
* Inhibitor
* Muscle regeneration
* Muscle stem cells
* Nicotinamide N-methyltransferase
* Satellite cells
* Therapeutics
|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6469996
}}
{{medline-entry
|title=Nicotinamide-N-methyltransferase controls behavior, neurodegeneration and lifespan by regulating neuronal autophagy.
|pubmed-url=https://pubmed.ncbi.nlm.nih.gov/30192747
|abstract=Nicotinamide N-methyl-transferase ([[NNMT]]) is an essential contributor to various metabolic and epigenetic processes, including the regulating of aging, cellular stress response, and body weight gain. Epidemiological studies show that [[NNMT]] is a risk factor for psychiatric diseases like schizophrenia and neurodegeneration, especially Parkinson's disease (PD), but its neuronal mechanisms of action remain obscure. Here, we describe the role of neuronal [[NNMT]] using C. elegans. We discovered that ANMT-1, the nematode [[NNMT]] ortholog, competes with the methyltransferase LCMT-1 for methyl groups from S-adenosyl methionine. Thereby, it regulates the catalytic capacities of LCMT-1, targeting NPRL-2, a regulator of autophagy. Autophagy is a core cellular, catabolic process for degrading cytoplasmic material, but very little is known about the regulation of autophagy during aging. We report an important role for [[NNMT]] in regulation of autophagy during aging, where high neuronal ANMT-1 activity induces autophagy via NPRL-2, which maintains neuronal function in old wild type animals and various disease models, also affecting longevity. In younger animals, however, ANMT-1 activity disturbs neuronal homeostasis and dopamine signaling, causing abnormal behavior. In summary, we provide fundamental insights into neuronal [[NNMT]]/ANMT-1 as pivotal regulator of behavior, neurodegeneration, and lifespan by controlling neuronal autophagy, potentially influencing PD and schizophrenia risk in humans.
|mesh-terms=* Animals
* Animals, Genetically Modified
* Autophagy
* Behavior, Animal
* Caenorhabditis elegans
* Caenorhabditis elegans Proteins
* Disease Models, Animal
* Dopamine
* Humans
* Longevity
* Methyltransferases
* Mutagenesis, Site-Directed
* Neurodegenerative Diseases
* Neurons
* Nicotinamide N-Methyltransferase
* S-Adenosylmethionine

|full-text-url=https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6191153
}}