MOTS-c and Cardiovascular Adaptations to Exercise

by Dr. James Ross

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Background

MOTS-c (mitochondrial open reading frame of the 12S rRNA type-c) is a mitochondrial-derived signaling peptide involved in metabolic regulation. It is detectable in multiple tissues and in circulation, leading to its description as a mitochondrial hormone. Its physiological role includes activation of AMP-activated protein kinase (AMPK) and modulation of nuclear gene expression. Previous research has primarily addressed MOTS-c in pathological cardiovascular conditions, but its interaction with structured aerobic exercise in promoting physiological cardiac adaptation remains under investigation.

Study Design and Methods

Twenty-four male Sprague–Dawley rats (6 weeks old) were randomized into three groups: control (C), exercise training (E), and exercise training with MOTS-c administration (ME). Exercise consisted of treadmill running for 60 minutes per day, five days per week, over 12 weeks. The ME group received intraperitoneal MOTS-c (0.5 mg/kg/day), while control and exercise-only groups received saline. Cardiac structure and function were evaluated using echocardiography, Millar catheter hemodynamic monitoring, histology, and electron microscopy.

Anthropometric and Cardiac Indices

Rats undergoing exercise (E and ME) demonstrated lower body weight compared with sedentary controls. Heart wet weight and heart weight index (HWI), indicators of cardiac hypertrophy, were significantly increased in exercised groups relative to control. No significant differences in HWI were observed between the E and ME groups, suggesting that MOTS-c did not augment hypertrophy beyond that induced by training.

Histological and Structural Observations

Histopathological assessment revealed that exercise led to thickened myocardial fibers and closer cellular arrangement. The combination of exercise and MOTS-c maintained normal fiber alignment and staining with evidence of hypertrophy but preserved structural integrity. Cross-sectional area of cardiomyocytes was increased in both E and ME groups compared with control, but no significant difference was noted between E and ME, indicating that MOTS-c did not further enlarge cardiomyocyte size beyond exercise effects.

Echocardiographic and Functional Outcomes

Exercise training improved end-diastolic volume, ejection fraction, and fractional shortening compared to control. MOTS-c administration alongside exercise lowered resting heart rate and further enhanced ejection fraction. However, most measures of cardiac geometry and function (LVIDd, E/A ratio) did not differ significantly between exercise alone and exercise with MOTS-c, suggesting parallel benefits rather than additive effects.

Hemodynamic Findings

Hemodynamic monitoring showed that stroke work, cardiac output, and contractility indices were elevated in both E and ME groups compared with controls. Notably, while exercise alone improved additional parameters such as maximum power and diastolic relaxation, the ME group demonstrated lower values for these compared to exercise alone. This indicates that MOTS-c may selectively modulate myocardial mechanics, enhancing efficiency while attenuating excessive workload.

Molecular Insights

Both exercise and MOTS-c increased myocardial MOTS-c content. Exogenous administration amplified endogenous MOTS-c expression in cardiac tissue beyond exercise-induced levels. This was accompanied by increased phosphorylation of AMPK without changes in total AMPK protein, indicating activation rather than upregulation. These findings align with prior studies showing AMPK activation as a central mechanism for MOTS-c-mediated metabolic adaptation.

Clinical Relevance of MOTS-c

MOTS-c represents a novel therapeutic target with potential implications in exercise physiology and cardiovascular health. It promotes mitochondrial biogenesis, enhances glucose utilization, reduces insulin resistance, and modulates AMPK signaling pathways. Importantly, exogenous MOTS-c appears to complement exercise by improving systolic performance, supporting diastolic function, and enhancing myocardial efficiency.

Implications for Aging and Metabolic Health

Beyond cardiovascular effects, MOTS-c is implicated in the regulation of cellular senescence. By activating AMPK and downstream metabolic regulators, it may delay age-related functional decline, enhance stress resistance, and support extended lifespan. Studies in humans and animals indicate that endogenous MOTS-c levels rise with exercise, but exogenous administration produces more robust and sustained increases. This dual effect highlights its therapeutic potential in both athletic performance and age-associated disease prevention.

REFERENCES 

1. Yuan, J., Wang, M., Pan, Y. et al. The mitochondrial signaling peptide MOTS-c improves myocardial performance during exercise training in rats. Sci Rep 11, 20077 (2021). https://doi.org/10.1038/s41598-021-99568-3

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