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The mitochondrial signaling peptide MOTS-c improves myocardial performance during exercise training in rats
How Does MOTS-c Affect Performance?
It is widely accepted that regular physical activity is beneficial for cardiovascular health. Frequent exercise is robustly associated with a decrease in cardiovascular mortality as well as the risk of developing cardiovascular disease (CVD).
Physically active individuals have lower blood pressure, higher insulin sensitivity, and a more favorable plasma lipoprotein profile. Animal models of exercise show that repeated physical activity suppresses atherogenesis and increases the availability of vasodilatory mediators such as nitric oxide. Exercise has also been found to have beneficial effects on the heart. Acutely, exercise increases cardiac output and blood pressure, but individuals adapted to exercise show lower resting heart rate and cardiac hypertrophy.
MOTS-c (mitochondrial ORF of the 12S rRNA type-c) is an MDP that promotes metabolic homeostasis, in part, via AMPK and by directly regulating adaptive nuclear gene expression following nuclear translocation. MOTS-c expression is age-dependent and detected in multiple tissues, including skeletal muscle, and in circulation, thus it has been dubbed a “mitochondrial hormone” or “mitokine”
The cardiovascular effects of MOTS-c have mostly focused on cardiovascular effects such as coronary endothelial dysfunction and pathological myocardial remodeling. However, the combined effects of MOTS-c and aerobic exercise on physiological myocardial remodeling has not been reported.
Researchers examined the effects of MOTS-c on cardiac function (using Millar carotid catheter monitoring) and structure (using hematoxylin–eosin (HE) staining, transmission electron microscopy, and echocardiography) in rats exposed to chronic aerobic exercise. In addition, they also explored whether MOTS-c enhanced physiological cardiac adaptations to exercise training. Their findings provide an experimental basis for the use of putative exercise supplements to modulate the cardiovascular benefits of athletic training.
Experimental animals
Twenty-four male Sprague–Dawley rats (6 weeks old) were used in the study. The animals were housed 5 to a standard rodent cage, maintained on a 12-h light /12-h dark cycle, and allowed access to food and water ad libitum. The animal room temperature was 21 °C–23 °C, and relative humidity was 40–60%.
“The rats were randomly divided into three equal sized groups (8 rats per group): control (C), exercise training (E), exercise training combined with MOTS-c treatment (ME).
Intervention protocols
Exercise training
All rats in the E and ME groups were adaptively trained on a treadmill (DSPT-208, Duan Animal Treadmill Co. Ltd, Hangzhou, China) for 1 week. In the formal exercise intervention, the treadmill started at a speed of 10 m/min, and gradually increased to 20 m/min at an inclination of + 10°. The exercise training lasted for 60 min per session and occurred 5 days a week for 12 weeks.
MOTS-c treatment
Rats were administered with MOTS-c and saline half an hour before the start of the exercise protocol. Rats in the ME group were administered intraperitoneally (i.p.) with MOTS-c (0.5 mg/kg/day) for 12 weeks, while those in the C and E groups were treated with saline (0.5 mg/kg/day intraperitoneally) for 12 weeks.”
Results
Body weight, heart wet weight and heart weight index (HWI). The changes in body weight (A) and heart wet weight (B) of rats in the control group, exercise group and MOTS-c combined exercise group were detected. Calculate the heart wet weight/body weight (HWI) ratio (C) to evaluate the growth response of the heart with or without MOTS-c administration during exercise. *p < 0.05, **p < 0.01, compared to group C.
“Myocardial muscle fibers were continuous and complete in rats from group C, with clear structures and uniform staining, and no abnormal changes in myocardial nuclei. However, the gaps between myocardial cells were widened in rats from group E, where myocardial fibers were thickened, and myocardial cells arranged more closely. The myocardial fiber structure was clear and thickened and tended to be hypertrophied in rats from group ME, with their muscle fibers running normally with uniform staining, clear transverse striations, and no significant nuclear changes. Exercise training and MOTS-c combined exercise training increased the cross-sectional area (CSA) of myocardial muscle fibers compared to the control group. Values for CSA in rats from groups E and ME (p < 0.001, p < 0.001) were higher than in group C, while CSA (p = 0.514) was similar in groups E and ME (Fig. 2A,B)”
The effects of MOTS-c and exercise training on rat myocardial structure and hypertrophic genes. (A) is the HE staining (× 400) and TEM (× 20,000) images of the myocardium, which respectively reflect the gross and ultrastructure of the myocardium. The arrow is the lysosome. (B) Quantification of cross-sectional area of cardiomyocytes from H&E-stained sections. (C) Quantitative analysis of the number of myocardial mitochondria in TEM. (D and E) The mRNA expression of ANP and BNP. *p < 0.05, **p < 0.01, compared to group C. C = Control, E = Exercise training, ME = Exercise training combined with MOTS-c treatment.
Changes of cardiac structure and function after MOTS-c. (A) The HR in group ME was lower than in group C. (B) There were no differences in LVIDd among these three groups; (C) The EDV in group E and ME was higher than in group C; (D)There were no differences in E/A among these three groups; (E) The EF in group E and ME was significantly higher than in group C; (F) The FS in group E was higher than in group C. *p < 0.05, **p < 0.01, compared to group C. #p < 0.05, compared to group E.
Baseline hemodynamic data
“Baseline measures of hemodynamic data includes indices of cardiac systolic function such as SW, CO, EF, dP/dtmax and Powmax. The indices of diastolic function include dP / dtmin and Tau. Ea (arterial elasticity) integrates key elements of arterial load, including peripheral vascular resistance, common arterial compliance, characteristic impedance, systolic and diastolic time intervals.
Values for SW (p < 0.001) , CO (p < 0.001), EF (p = 0.003) and dP/dtmax (p < 0.001) in rats from groups E and ME were higher than in group C. Powmax (p = 0.002 and dP/dtmin (p < 0.001) in group E was also higher than in group C. Ea (p < 0.001)in groups E and ME were lower than in group C, while there were no differences in Tau between group C and E (p = 0.693). EF in group ME was greater (p = 0.005), while values for Powmax (p = 0.004), dP/dtmin (p = 0.004) and Tau (p < 0.001) were lower than in group C. Values for SW (p < 0.001), CO (p < 0.001), Powmax (p < 0.001), dP /dtmin (p < 0.001) and Tau (p < 0.001) in group ME were lower than in group E, while EF (p = 0.639), Ea (p = 0.064) and dP/dtmax (p = 0.104) was similar in groups E and ME.”
Changes in cardiac hemodynamics after MOTS-c treatment during exercise training. Baseline P–V-loops and after blood flow in the inferior vena cava blood flow was obstructed. Stroke work and the slope of ESPVR (C) [Ees (end-systolic elastance)] in the E and ME were significantly higher than in group C. (C = Control, E = Exercise training, ME = Exercise training combined with MOTS-c treatment).
Changes in the protein expression of MOTS-c, p-AMPK, and t-AMPK in each group of rats. (A and B) are the representative images of MOTS-c, p-AMPK(Thr172), t-AMPK. (C) is the change of MOTS-c compared to β-Actin multiple. (D) is stoichiometric AMPK phosphorylation (phosphor/total ratio). *p < 0.05, **p < 0.01, compared to group C. #p < 0.05, ##p < 0.01, compared to group E. (C = Control, E = Exercise training, ME = Exercise training combined with MOTS-c treatment).
“The findings of Lee et al. indicated that mice had higher levels of MOTS-c than humans. They reported that levels of MOTS-c were increased in the myocardium, skeletal muscle and brain, and that exercised endogenous levels of MOTS-c. Another study by Reynolds et al. reported that levels of endogenous MOTS-c in humans increased by 1.5 times after exercise, which is consistent with the results of our study. Surprisingly, after we administered MOTS-c into exercise-trained rats, the endogenous MOTS-c rose more robustly, indicating that exogenous was transformed into endogenous MOTS-c, confirming the finding of Kim et al. that endogenous MOTS-c increased after MOTS-c treatment.
We also found that increased levels of endogenous MOTS-c in the myocardium in rats from the ME group activated AMPK and increased phosphorylated AMPK, while the total amount remained unchanged. Activated AMPK regulates other proteins to improve cardiac performance. A study by Lee et al. also found that p-AMPK increased after MOTS-c treatment, while t-AMPK remained unchanged. Our study indicates that administering exogenous MOTS-c increases endogenous levels of MOTS-c of the myocardium, which in turn slightly activates AMPK.”
MOTS-c is a mitochondrial-derived peptide that is primarily being researched for fat loss, but has also shown efficacy for muscle building, improved physical performance, and as an anti-aging peptide by reversing cellular senescence*. Interestingly, the long-lived Japanese people (population with the most extended lifespan in the world) have demonstrated the phenotypic expression and biological link between MOTS-c and an extended lifespan.
How does MOTS-c work?
MOTS-c functions to activate the mitochondrial genome, thereby increasing mitochondrial biogenesis. This process all happens through the inhibition of the methionine-folate cycle, resulting in purine synthesis and increased PCG-1 alpha and AICAR, all of which play vital roles in energy metabolism via AMP-activated protein kinase (AMPK). By stimulating AMPK, *cellular senescence is, in part, reversed.
MOTS-c has been shown to decrease insulin resistance, accelerate the transport of sugars into muscle cells, aid in fat loss, increase energy and resistance to metabolic stress, and improve overall health and lifespan.
What is Cellular Senescence?
When cells are damaged, they sense their damage, and they can pause. This process is called cellular senescence or cellular arrest. Cells are programmed to do this because they don’t want to replicate with damage. Instead, they pause until the immune system can clear them. Until cleared, senescent cells secrete signals that cause harm to the body. These signals increase inflammation, exhaust stem cells, and cause the body to age more rapidly. While senescence is natural, clearing senescent cells is vital to stop the aging process.
How Does MOTS-c Affect Performance?
It is widely accepted that regular physical activity is beneficial for cardiovascular health. Frequent exercise is robustly associated with a decrease in cardiovascular mortality as well as the risk of developing cardiovascular disease (CVD).
Physically active individuals have lower blood pressure, higher insulin sensitivity, and a more favorable plasma lipoprotein profile. Animal models of exercise show that repeated physical activity suppresses atherogenesis and increases the availability of vasodilatory mediators such as nitric oxide. Exercise has also been found to have beneficial effects on the heart. Acutely, exercise increases cardiac output and blood pressure, but individuals adapted to exercise show lower resting heart rate and cardiac hypertrophy.
MOTS-c (mitochondrial ORF of the 12S rRNA type-c) is an MDP that promotes metabolic homeostasis, in part, via AMPK and by directly regulating adaptive nuclear gene expression following nuclear translocation. MOTS-c expression is age-dependent and detected in multiple tissues, including skeletal muscle, and in circulation, thus it has been dubbed a “mitochondrial hormone” or “mitokine”
The cardiovascular effects of MOTS-c have mostly focused on cardiovascular effects such as coronary endothelial dysfunction and pathological myocardial remodeling. However, the combined effects of MOTS-c and aerobic exercise on physiological myocardial remodeling has not been reported.
Researchers examined the effects of MOTS-c on cardiac function (using Millar carotid catheter monitoring) and structure (using hematoxylin–eosin (HE) staining, transmission electron microscopy, and echocardiography) in rats exposed to chronic aerobic exercise. In addition, they also explored whether MOTS-c enhanced physiological cardiac adaptations to exercise training. Their findings provide an experimental basis for the use of putative exercise supplements to modulate the cardiovascular benefits of athletic training.
Experimental animals
Twenty-four male Sprague–Dawley rats (6 weeks old) were used in the study. The animals were housed 5 to a standard rodent cage, maintained on a 12-h light /12-h dark cycle, and allowed access to food and water ad libitum. The animal room temperature was 21 °C–23 °C, and relative humidity was 40–60%.
“The rats were randomly divided into three equal sized groups (8 rats per group): control (C), exercise training (E), exercise training combined with MOTS-c treatment (ME).
Intervention protocols
Exercise training
All rats in the E and ME groups were adaptively trained on a treadmill (DSPT-208, Duan Animal Treadmill Co. Ltd, Hangzhou, China) for 1 week. In the formal exercise intervention, the treadmill started at a speed of 10 m/min, and gradually increased to 20 m/min at an inclination of + 10°. The exercise training lasted for 60 min per session and occurred 5 days a week for 12 weeks.
MOTS-c treatment
Rats were administered with MOTS-c and saline half an hour before the start of the exercise protocol. Rats in the ME group were administered intraperitoneally (i.p.) with MOTS-c (0.5 mg/kg/day) for 12 weeks, while those in the C and E groups were treated with saline (0.5 mg/kg/day intraperitoneally) for 12 weeks.”
Results
Changes of body weight and heart weight index after MOTS-c treatment during exercise training
“The body weight (BW) of rats in groups E and ME were significantly lower than those in group C (p = 0.003, p = 0.009), and the BW of rats was similar for rats in groups ME and E (p = 0.359). (Fig. 1A). The wet weights for hearts from rats in groups ME (p = 0.015) were greater than in group C (p = 0.061), while wet weights were similar for hearts from rats in groups E and ME (p = 0.565). (Fig. 1B). The heart weight index (HWI) is a useful preliminary indicator of cardiac hypertrophy. HWI of rats in groups E (p = 0.001) and ME (p = 0.001) were greater than in group C, with no differences between HWI of rats in groups E and ME (p = 0.805) (Fig. 1C).”Body weight, heart wet weight and heart weight index (HWI). The changes in body weight (A) and heart wet weight (B) of rats in the control group, exercise group and MOTS-c combined exercise group were detected. Calculate the heart wet weight/body weight (HWI) ratio (C) to evaluate the growth response of the heart with or without MOTS-c administration during exercise. *p < 0.05, **p < 0.01, compared to group C.
Cardiac histology after MOTS-c treatment during exercise training
Hematoxylin–Eosin“Myocardial muscle fibers were continuous and complete in rats from group C, with clear structures and uniform staining, and no abnormal changes in myocardial nuclei. However, the gaps between myocardial cells were widened in rats from group E, where myocardial fibers were thickened, and myocardial cells arranged more closely. The myocardial fiber structure was clear and thickened and tended to be hypertrophied in rats from group ME, with their muscle fibers running normally with uniform staining, clear transverse striations, and no significant nuclear changes. Exercise training and MOTS-c combined exercise training increased the cross-sectional area (CSA) of myocardial muscle fibers compared to the control group. Values for CSA in rats from groups E and ME (p < 0.001, p < 0.001) were higher than in group C, while CSA (p = 0.514) was similar in groups E and ME (Fig. 2A,B)”
The effects of MOTS-c and exercise training on rat myocardial structure and hypertrophic genes. (A) is the HE staining (× 400) and TEM (× 20,000) images of the myocardium, which respectively reflect the gross and ultrastructure of the myocardium. The arrow is the lysosome. (B) Quantification of cross-sectional area of cardiomyocytes from H&E-stained sections. (C) Quantitative analysis of the number of myocardial mitochondria in TEM. (D and E) The mRNA expression of ANP and BNP. *p < 0.05, **p < 0.01, compared to group C. C = Control, E = Exercise training, ME = Exercise training combined with MOTS-c treatment.
Changes of cardiac structure and function after MOTS-c treatment during exercise training
“Values for EDV(p = 0.005), EF (p = 0.001) and FS (p = 0.033) in group E were higher than that in group C, but with no differences in HR, LVIDd and E/A between groups E and C (p = 0.146, p = 0.256, p = 0.796). The HR in group ME was lower than in group C (p = 0.021), while EDV and EF in group ME was higher than in group C (p = 0.015, p < 0.001), with no differences in LVIDd (p = 0.691), E/A (p = 0.861) and FS (p = 0.142). There were no differences in HR (p = 0.204), LVIDd(p = 0.133), EDV(p = 0.370), E/A (p = 0.667), EF (p = 0.509), FS (p = 0.374) between groups E and ME. (Figs. 3 and 4).”Changes of cardiac structure and function after MOTS-c. (A) The HR in group ME was lower than in group C. (B) There were no differences in LVIDd among these three groups; (C) The EDV in group E and ME was higher than in group C; (D)There were no differences in E/A among these three groups; (E) The EF in group E and ME was significantly higher than in group C; (F) The FS in group E was higher than in group C. *p < 0.05, **p < 0.01, compared to group C. #p < 0.05, compared to group E.
Baseline hemodynamic data
“Baseline measures of hemodynamic data includes indices of cardiac systolic function such as SW, CO, EF, dP/dtmax and Powmax. The indices of diastolic function include dP / dtmin and Tau. Ea (arterial elasticity) integrates key elements of arterial load, including peripheral vascular resistance, common arterial compliance, characteristic impedance, systolic and diastolic time intervals.
Values for SW (p < 0.001) , CO (p < 0.001), EF (p = 0.003) and dP/dtmax (p < 0.001) in rats from groups E and ME were higher than in group C. Powmax (p = 0.002 and dP/dtmin (p < 0.001) in group E was also higher than in group C. Ea (p < 0.001)in groups E and ME were lower than in group C, while there were no differences in Tau between group C and E (p = 0.693). EF in group ME was greater (p = 0.005), while values for Powmax (p = 0.004), dP/dtmin (p = 0.004) and Tau (p < 0.001) were lower than in group C. Values for SW (p < 0.001), CO (p < 0.001), Powmax (p < 0.001), dP /dtmin (p < 0.001) and Tau (p < 0.001) in group ME were lower than in group E, while EF (p = 0.639), Ea (p = 0.064) and dP/dtmax (p = 0.104) was similar in groups E and ME.”
Changes in cardiac hemodynamics after MOTS-c treatment during exercise training. Baseline P–V-loops and after blood flow in the inferior vena cava blood flow was obstructed. Stroke work and the slope of ESPVR (C) [Ees (end-systolic elastance)] in the E and ME were significantly higher than in group C. (C = Control, E = Exercise training, ME = Exercise training combined with MOTS-c treatment).
Exogenous administration of MOTS-c during exercise can increase the endogenous MOTS-c of the myocardium and activate AMPK
“The content of MOTS-c in groups E and ME were higher (p = 0.020, p < 0.001) than in group C, and the levels of MOTS-c of group ME after exogenous administration of MOTS-c was also significantly higher than that of group E (p = 0.009). Levels of p-AMPK in group ME was significantly increased compared to group C (p = 0.021), while there were no changes in group E (p = 0.108). There was no difference in p-AMPK between groups E and ME (p = 0.270). There were no significant differences in values for t-AMPK between the group C and group E, ME (p = 0.833, p = 0.583), and with no differences between the groups E and ME (p = 0.731). AMPK phosphorylation (phosphor/total) in group ME was significantly higher than that in group C (p = 0.009), while there were no significant differences in AMPK phosphorylation among group C, E and ME (E vs. C, p = 0.051; E vs. ME, p = 0.233) It seems that exercise combined with MOTS-c treatment activate AMPK, instead of increasing total AMPK protein expression (Fig. 6).”Changes in the protein expression of MOTS-c, p-AMPK, and t-AMPK in each group of rats. (A and B) are the representative images of MOTS-c, p-AMPK(Thr172), t-AMPK. (C) is the change of MOTS-c compared to β-Actin multiple. (D) is stoichiometric AMPK phosphorylation (phosphor/total ratio). *p < 0.05, **p < 0.01, compared to group C. #p < 0.05, ##p < 0.01, compared to group E. (C = Control, E = Exercise training, ME = Exercise training combined with MOTS-c treatment).
“The findings of Lee et al. indicated that mice had higher levels of MOTS-c than humans. They reported that levels of MOTS-c were increased in the myocardium, skeletal muscle and brain, and that exercised endogenous levels of MOTS-c. Another study by Reynolds et al. reported that levels of endogenous MOTS-c in humans increased by 1.5 times after exercise, which is consistent with the results of our study. Surprisingly, after we administered MOTS-c into exercise-trained rats, the endogenous MOTS-c rose more robustly, indicating that exogenous was transformed into endogenous MOTS-c, confirming the finding of Kim et al. that endogenous MOTS-c increased after MOTS-c treatment.
We also found that increased levels of endogenous MOTS-c in the myocardium in rats from the ME group activated AMPK and increased phosphorylated AMPK, while the total amount remained unchanged. Activated AMPK regulates other proteins to improve cardiac performance. A study by Lee et al. also found that p-AMPK increased after MOTS-c treatment, while t-AMPK remained unchanged. Our study indicates that administering exogenous MOTS-c increases endogenous levels of MOTS-c of the myocardium, which in turn slightly activates AMPK.”
Conclusion
“Administration of exogenous MOTS-c increases endogenous levels of myocardial MOTS-c, improves the mechanical efficiency of the myocardium, strengthens the systolic function of the heart, and helps to improve diastolic function during exercise training. Our findings provide an experimental basis for the use of putative exercise supplements to further promote the cardiovascular benefits of exercise training.”Summary
What is MOTS-c?MOTS-c is a mitochondrial-derived peptide that is primarily being researched for fat loss, but has also shown efficacy for muscle building, improved physical performance, and as an anti-aging peptide by reversing cellular senescence*. Interestingly, the long-lived Japanese people (population with the most extended lifespan in the world) have demonstrated the phenotypic expression and biological link between MOTS-c and an extended lifespan.
How does MOTS-c work?
MOTS-c functions to activate the mitochondrial genome, thereby increasing mitochondrial biogenesis. This process all happens through the inhibition of the methionine-folate cycle, resulting in purine synthesis and increased PCG-1 alpha and AICAR, all of which play vital roles in energy metabolism via AMP-activated protein kinase (AMPK). By stimulating AMPK, *cellular senescence is, in part, reversed.
MOTS-c has been shown to decrease insulin resistance, accelerate the transport of sugars into muscle cells, aid in fat loss, increase energy and resistance to metabolic stress, and improve overall health and lifespan.
What is Cellular Senescence?
When cells are damaged, they sense their damage, and they can pause. This process is called cellular senescence or cellular arrest. Cells are programmed to do this because they don’t want to replicate with damage. Instead, they pause until the immune system can clear them. Until cleared, senescent cells secrete signals that cause harm to the body. These signals increase inflammation, exhaust stem cells, and cause the body to age more rapidly. While senescence is natural, clearing senescent cells is vital to stop the aging process.
