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Effects of 1-Methylnicotinamide (MNA) on Exercise Capacity and Endothelial Response in Diabetic Mice.

Przyborowski K, Wojewoda M, Sitek B, Zakrzewska A, Kij A, Wandzel K, Zoladz JA, Chlopicki S - PLoS ONE (2015)

Bottom Line: MNA treatment of db/db mice resulted in four-fold and three-fold elevation of urine concentrations of MNA and its metabolites (Met-2PY + Met-4PY), respectively (P<0.01), but did not affect HbA1c concentration, fasting glucose concentration or lipid profile.Post-exercise Δ6-keto-PGF1α (difference between mean concentration in the sedentary and exercised groups) tended to increase, and post-exercise leukocytosis was substantially reduced in MNA-treated animals.In turn, the post-exercise fall in plasma concentration of nitrate was not affected by MNA.

View Article: PubMed Central - PubMed

Affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland.

ABSTRACT
1-Methylnicotinamide (MNA), which was initially considered to be a biologically inactive endogenous metabolite of nicotinamide, has emerged as an anti-thrombotic and anti-inflammatory agent with the capacity to release prostacyclin (PGI2). In the present study, we characterized the effects of MNA on exercise capacity and the endothelial response to exercise in diabetic mice. Eight-week-old db/db mice were untreated or treated with MNA for 4 weeks (100 mg·kg-1), and their exercise capacity as well as NO- and PGI2-dependent response to endurance running were subsequently assessed. MNA treatment of db/db mice resulted in four-fold and three-fold elevation of urine concentrations of MNA and its metabolites (Met-2PY + Met-4PY), respectively (P<0.01), but did not affect HbA1c concentration, fasting glucose concentration or lipid profile. However, insulin sensitivity was improved (P<0.01). In MNA-treated db/db mice, the time to fatigue for endurance exercise was significantly prolonged (P<0.05). Post-exercise Δ6-keto-PGF1α (difference between mean concentration in the sedentary and exercised groups) tended to increase, and post-exercise leukocytosis was substantially reduced in MNA-treated animals. In turn, the post-exercise fall in plasma concentration of nitrate was not affected by MNA. In conclusion, we demonstrated for the first time that MNA improves endurance exercise capacity in mice with diabetes, and may also decrease the cardiovascular risk of exercise.

No MeSH data available.


Related in: MedlinePlus

Effect of MNA treatment on exercise capacity in db/db mice.Untreated db/db mice and db/db mice treated with MNA for 4 weeks were subjected to endurance running at 8 m·min-1 on a treadmill with 5° inclination. The graph shows Kaplan-Meier curves of running mice in percentage for the two experimental groups: untreated mice (dashed line) and MNA-treated mice (solid line). Censored observations are marked with circles or triangles for the untreated and MNA-treated groups, respectively. Running time analysis was performed with Kaplan-Meier estimation using the log-rank Mantel-Cox test (n = 10–12).
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pone.0130908.g004: Effect of MNA treatment on exercise capacity in db/db mice.Untreated db/db mice and db/db mice treated with MNA for 4 weeks were subjected to endurance running at 8 m·min-1 on a treadmill with 5° inclination. The graph shows Kaplan-Meier curves of running mice in percentage for the two experimental groups: untreated mice (dashed line) and MNA-treated mice (solid line). Censored observations are marked with circles or triangles for the untreated and MNA-treated groups, respectively. Running time analysis was performed with Kaplan-Meier estimation using the log-rank Mantel-Cox test (n = 10–12).

Mentions: As shown in Fig 4, db/db mice treated with MNA displayed improved exercise capacity as evidenced by the prolonged endurance running time (P = 0.025). Improved exercise capacity by MNA was not related to changes in post-exercise blood cell count, HCT, HGB, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) or triglycerides (TG) concentrations (Table 1, Fig 5). However, HCT significantly increased in post-exercise MNA-treated db/db mice (from 56.83±1.978 to 61.98±0.954%, P<0.05, n = 6–9), while post-exercise leukocytosis was substantially inhibited (for untreated mice, 3.150±0.452 vs. 1.367±0.226 K. μl-1, P<0.05, n = 8–6, and for MNA-treated mice, 2.100±0.298 vs. 2.350±0.343 vs. K. μl-1, for post-exercise and sedentary groups, respectively, n = 10–6, Table 1). Endurance exercise resulted in a substantial increase in MNA plasma concentration in untreated db/db mice (from 1.115±0.156 to 3.351±0.280 nmol·ml-1, P<0.001, n = 7–10, Fig 6A). In MNA-treated db/db mice, the post-exercise increase in MNA plasma concentration was also significant (from 3.019±0.918 to 5.479±0.328 nmol·ml-1, P<0.01, n = 7–11). Interestingly, the relative exercise-induced increase in the plasma MNA concentration was similar in both the MNA-treated and untreated db/db mice (Δ = 2.46 and Δ = 2.24 nmol·ml-1 in MNA-treated and untreated groups, respectively), although the pre-exercise MNA plasma concentration was approximately 2.5-fold higher in MNA-treated db/db mice as compared to untreated db/db mice (3.019±0.918 vs. 1.115±0.156 nmol·ml-1, P = 0.063, n = 7, Fig 6A). The pattern of exercise-induced changes in the plasma concentration of the MNA metabolites (Met-2PY and Met-4PY) was similar to that of MNA (Fig 6B).


Effects of 1-Methylnicotinamide (MNA) on Exercise Capacity and Endothelial Response in Diabetic Mice.

Przyborowski K, Wojewoda M, Sitek B, Zakrzewska A, Kij A, Wandzel K, Zoladz JA, Chlopicki S - PLoS ONE (2015)

Effect of MNA treatment on exercise capacity in db/db mice.Untreated db/db mice and db/db mice treated with MNA for 4 weeks were subjected to endurance running at 8 m·min-1 on a treadmill with 5° inclination. The graph shows Kaplan-Meier curves of running mice in percentage for the two experimental groups: untreated mice (dashed line) and MNA-treated mice (solid line). Censored observations are marked with circles or triangles for the untreated and MNA-treated groups, respectively. Running time analysis was performed with Kaplan-Meier estimation using the log-rank Mantel-Cox test (n = 10–12).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4482656&req=5

pone.0130908.g004: Effect of MNA treatment on exercise capacity in db/db mice.Untreated db/db mice and db/db mice treated with MNA for 4 weeks were subjected to endurance running at 8 m·min-1 on a treadmill with 5° inclination. The graph shows Kaplan-Meier curves of running mice in percentage for the two experimental groups: untreated mice (dashed line) and MNA-treated mice (solid line). Censored observations are marked with circles or triangles for the untreated and MNA-treated groups, respectively. Running time analysis was performed with Kaplan-Meier estimation using the log-rank Mantel-Cox test (n = 10–12).
Mentions: As shown in Fig 4, db/db mice treated with MNA displayed improved exercise capacity as evidenced by the prolonged endurance running time (P = 0.025). Improved exercise capacity by MNA was not related to changes in post-exercise blood cell count, HCT, HGB, total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) or triglycerides (TG) concentrations (Table 1, Fig 5). However, HCT significantly increased in post-exercise MNA-treated db/db mice (from 56.83±1.978 to 61.98±0.954%, P<0.05, n = 6–9), while post-exercise leukocytosis was substantially inhibited (for untreated mice, 3.150±0.452 vs. 1.367±0.226 K. μl-1, P<0.05, n = 8–6, and for MNA-treated mice, 2.100±0.298 vs. 2.350±0.343 vs. K. μl-1, for post-exercise and sedentary groups, respectively, n = 10–6, Table 1). Endurance exercise resulted in a substantial increase in MNA plasma concentration in untreated db/db mice (from 1.115±0.156 to 3.351±0.280 nmol·ml-1, P<0.001, n = 7–10, Fig 6A). In MNA-treated db/db mice, the post-exercise increase in MNA plasma concentration was also significant (from 3.019±0.918 to 5.479±0.328 nmol·ml-1, P<0.01, n = 7–11). Interestingly, the relative exercise-induced increase in the plasma MNA concentration was similar in both the MNA-treated and untreated db/db mice (Δ = 2.46 and Δ = 2.24 nmol·ml-1 in MNA-treated and untreated groups, respectively), although the pre-exercise MNA plasma concentration was approximately 2.5-fold higher in MNA-treated db/db mice as compared to untreated db/db mice (3.019±0.918 vs. 1.115±0.156 nmol·ml-1, P = 0.063, n = 7, Fig 6A). The pattern of exercise-induced changes in the plasma concentration of the MNA metabolites (Met-2PY and Met-4PY) was similar to that of MNA (Fig 6B).

Bottom Line: MNA treatment of db/db mice resulted in four-fold and three-fold elevation of urine concentrations of MNA and its metabolites (Met-2PY + Met-4PY), respectively (P<0.01), but did not affect HbA1c concentration, fasting glucose concentration or lipid profile.Post-exercise Δ6-keto-PGF1α (difference between mean concentration in the sedentary and exercised groups) tended to increase, and post-exercise leukocytosis was substantially reduced in MNA-treated animals.In turn, the post-exercise fall in plasma concentration of nitrate was not affected by MNA.

View Article: PubMed Central - PubMed

Affiliation: Jagiellonian Centre for Experimental Therapeutics (JCET), Jagiellonian University, Krakow, Poland.

ABSTRACT
1-Methylnicotinamide (MNA), which was initially considered to be a biologically inactive endogenous metabolite of nicotinamide, has emerged as an anti-thrombotic and anti-inflammatory agent with the capacity to release prostacyclin (PGI2). In the present study, we characterized the effects of MNA on exercise capacity and the endothelial response to exercise in diabetic mice. Eight-week-old db/db mice were untreated or treated with MNA for 4 weeks (100 mg·kg-1), and their exercise capacity as well as NO- and PGI2-dependent response to endurance running were subsequently assessed. MNA treatment of db/db mice resulted in four-fold and three-fold elevation of urine concentrations of MNA and its metabolites (Met-2PY + Met-4PY), respectively (P<0.01), but did not affect HbA1c concentration, fasting glucose concentration or lipid profile. However, insulin sensitivity was improved (P<0.01). In MNA-treated db/db mice, the time to fatigue for endurance exercise was significantly prolonged (P<0.05). Post-exercise Δ6-keto-PGF1α (difference between mean concentration in the sedentary and exercised groups) tended to increase, and post-exercise leukocytosis was substantially reduced in MNA-treated animals. In turn, the post-exercise fall in plasma concentration of nitrate was not affected by MNA. In conclusion, we demonstrated for the first time that MNA improves endurance exercise capacity in mice with diabetes, and may also decrease the cardiovascular risk of exercise.

No MeSH data available.


Related in: MedlinePlus