Abstract Th0080: Inhibition of Nicotinamide N-Methyltransferase Enhances Limb Function in Experimental Peripheral Artery Disease

Introduction: Peripheral artery disease (PAD) affects approximately 200 million people worldwide. Nicotinamide N-methyltransferase (NNMT), a key metabolic enzyme, regulates nicotinamide adenine dinucleotide (NAD+) bioavailability. Elevated levels of NNMT may lead to decreased bioavailability of NAD+, a key electron carrier for oxidative metabolism. Recent findings have revealed the upregulation of NNMT at both the mRNA and protein levels in the skeletal muscle of severe PAD patients, which could contribute to the mitochondrial deficiencies observed by the muscle of these patients. This study aimed to evaluate the effects of NNMT inhibition on muscle function using a preclinical model of PAD. Methods: Male Balb/cJ mice (N=24) were used. PAD was induced via femoral artery ligation surgery. The NNMTi or placebo (10 mg/kg/day) was administered intraperitoneally once daily for 21 days. The first treatment was given three hours prior to the surgery. A 6-minute limb function test was performed to evaluate limb function. Results: Compared to placebo group, NNMTi group had significantly higher absolute and specific (normalized to muscle mass) force ( P <0.001 and P =0.004, respectively). Similarly, muscle power output was significantly greater in NNMTi group ( P =0.03). Employing a novel 6-minute limb function test, NNMTi group performed significantly more work compared to placebo group ( P =0.04). Resting paw perfusion recovery, measured via laser Doppler imaging, was not different between the groups ( P =0.37). The hyperemic response during the 6-minute limb function test was higher in NNMTi group (Placebo group: 211.9 ± 11.38 vs. NNMTi group: 297.9±13.82), although this did not reach statistical significance ( P =0.13). Muscle mass was not different between the NNMTi and placebo groups, indicating that NNMTi treatment enhances muscle function without directly affecting muscle mass. Conclusion: These findings demonstrate that NNMT inhibition significantly improves muscle function in experimental PAD, as evidenced by enhanced muscle strength, power, and work, independent of changes in muscle mass or blood flow. These results align with clinical trials providing treatments that use other approaches to enhance the bioavailability of NAD+ in PAD patients, further highlighting the potential therapeutic value of NNMT inhibition as an alternative or adjuvant strategy for improving muscle metabolism and enhancing limb function in PAD.