NNMTi is a potent inhibitor of nicotinamide N-methyltransferase (NNMT), with an IC50 of 1.2 μM, selectively targeting the substrate-binding site residues of NNMT[2]. NNMTi enhances myoblast differentiation in vitro and improves the fusion and regenerative capabilities of muscle stem cells (muSCs) in aged mice[1].
体内研究
NNMTi, administered via subcutaneous injection at doses of 5 mg/kg and 10 mg/kg for two weeks (1 week pre-injury and 1 week post-injury), enhances muscle regeneration following injury. It leads to a 60% and 75% higher incidence of proliferating/active muscle stem cells (muSCs) at doses of 5 mg/kg and 10 mg/kg, respectively. The proportion of fibers with an EdU+ myonucleus increased by 40% and 48% under NNMTi treatment at 5 mg/kg and 10 mg/kg, respectively. The odds ratio of fused myonuclei for control is 0.58 and 0.53 times the odds at the lower and higher NNMTi doses, respectively[2].
NNMTi (subcutaneous injection; 10 mg/kg; 1 week) shows no systemic toxicity in mice. There are no significant differences in glucose, cholesterol, plasma proteins, and electrolytes between control and NNMTi-treated mice. Additionally, daily repeat dosing of NNMTi for one week post-injury is well tolerated, with no adverse systemic toxicity or behavioral effects in aged mice[2].
体外研究
NNMTi (10-30 μM; 96 hours) induces a dose-dependent increase in myoblast differentiation in C2C12 cells. At 30 μM, NNMTi leads to 18% MHC-positive myotube nuclei, reflecting a 45% enhancement in myoblast differentiation compared to untreated differentiating myoblasts, which show 12% MHC-positive myotube nuclei[1].
NNMTi 细胞实验
Cell Line
Concentration
Treated Time
Description
References
C2C12 myotubes
10 and 30 µM
24 hours
To evaluate the effect of NNMTi on NAD+/NADH redox states in C2C12 myotubes. Results showed that NNMTi treatment increased NADH levels by 50% and decreased NAD+/NADH ratio by 40%.
Biochem Pharmacol. 2019 May;163:481-492
C2C12 myoblasts
10 and 30 µM
24 hours
To evaluate the effect of NNMTi on C2C12 myoblast differentiation. Results showed that 30 µM NNMTi treatment increased MHC-positive myotube nuclei by 45%, indicating enhanced myoblast differentiation.
Biochem Pharmacol. 2019 May;163:481-492
RCC2
50 µM
24 hours
NNMTi alone or in combination with 2-DG or BPTES significantly reduced the viability of RCC2 cells.
Clin Transl Med. 2022 Jun;12(6):e883
RCC1
50 µM
24 hours
NNMTi alone or in combination with 2-DG or BPTES significantly reduced the viability of RCC1 cells.
Clin Transl Med. 2022 Jun;12(6):e883
A498
100 µM
24 hours
NNMTi at the highest tested dose significantly inhibited the viability of A498 cells.
Clin Transl Med. 2022 Jun;12(6):e883
786-O
50 µM and 100 µM
24 hours
NNMTi alone or in combination with 2-DG or BPTES significantly reduced the viability of 786-O cells.
Clin Transl Med. 2022 Jun;12(6):e883
NNMTi 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
BALB/c nude mice
NSCLC osimertinib-resistant xenograft model
Intraperitoneal injection
10 mg/kg/day
Once daily until the end of the experiment
NNMTi alone or in combination with osimertinib significantly inhibited tumor growth, reducing tumor volume and weight
Mol Cancer. 2025 Mar 15;24(1):79
Mice
Aged mouse model
Subcutaneous injection
10 mg/kg
Once daily for eight weeks
To evaluate the effects of NNMTi treatment and exercise interventions on age-associated muscle function. NNMTi-treated aged sedentary mice showed ~ 40% greater grip strength than sedentary controls, while aged exercised mice only showed a 20% increase relative to controls. The grip strength improvements resulting from NNMTi treatment and exercise were additive, with NNMTi-treated exercised mice developing a 60% increase in grip strength relative to sedentary controls. NNMTi treatment also promoted quantifiable improvements in IMCL content and, in combination with exercise, significantly increased gastrocnemius fiber CSA.
Sci Rep. 2024 Jul 5;14(1):15554
Mice
Diet-induced obese mouse model
Intraperitoneal injection
4 mg/mL, 10 µL/g
Daily administration for 7 weeks
NNMTi treatment combined with a lean diet switch accelerated and improved body weight and fat loss, increased whole-body lean mass to body weight ratio, reduced liver and epididymal white adipose tissue (EWAT) weights, decreased liver adiposity, and improved hepatic steatosis, relative to a lean diet substitution alone. Importantly, combined lean diet and NNMTi treatment normalized body composition and liver adiposity parameters to levels observed in age-matched lean diet control mice.
Sci Rep. 2021 Mar 11;11(1):5637
Mice
Aged mouse muscle injury model
Subcutaneous injection
5 and 10 mg/kg
Twice daily for 1 week or 3 weeks
To evaluate the effect of NNMTi on muscle regeneration in aged mice. Results showed that NNMTi treatment significantly increased muscle stem cell proliferation and fusion, promoted a nearly 2-fold increase in muscle fiber cross-sectional area, and improved muscle contractile function by ~70%.
Biochem Pharmacol. 2019 May;163:481-492
C57BL6 mice
D-galactose-induced aging mouse model
Intraperitoneal injection
5 or 10 mg/kg/d
Once daily for 5 weeks
Evaluate the effect of NNMTi on muscle strength and muscle mass in aging mice, results showed NNMTi improved muscle strength and muscle mass
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