MOTS-c 59 min read January 28, 2026

MOTS-c Review

1. **Metabolic Disorders**: MOTS-c's capacity to enhance insulin sensitivity and ameliorate glucose metabolism offers promising avenues for addressing metabolic disorders. Studies suggest its potential in mitigating the underlying pathophysiological processes associated with conditions like type 2 diabetes and obesity. 2. **Health Issues Related to Aging**: Age-related ailments are often linked to mitochondrial dysfunction and oxidative stress. MOTS-c's ability to uphold mitochondrial integrity

MOTS-c Review

A Brief Review of MOTS-c

Within the human mitochondrial DNA (mtDNA), there are 37 established genes, comprising 2 rRNAs, 22 tRNAs, and 13 polypeptide components essential for the electron transport chain (ETC) complexes. Recent research has brought to light the existence of small open reading frames (ORFs) in the rRNA regions, which can be transcribed and translated into short peptides known as mitochondrial-derived peptides (MDPs) with biological functions. Among these, MOTS-c is a peptide encoded by the mitochondrial DNA, encompassing 16 amino acids and originating from the 12S rRNA region of mtDNA within human cells.

MOTS-c possesses the ability to migrate to the cell nucleus in response to metabolic stress, influencing the regulation of adaptive nuclear gene expression. This property allows the peptide to enhance resistance to metabolic stress by increasing mitochondrial genome activity, thereby encouraging the production of more mitochondrial genes, a process known as mitochondrial biogenesis. Additionally, MOTS-c inhibits the methionine-folate cycle, resulting in reduced purine synthesis, an increase in PCG-1α (a critical regulator of energy metabolism), and the accumulation of AICAR (5-Aminoimidazole-4-carboxamide ribonucleotide), which activates AMPK (5'-adenosine monophosphate-activated protein kinase). AMPK functions as an energy sensor by monitoring the AMP-to-ATP ratio, restoring cellular balance by initiating catabolic processes to produce ATP when energy is scarce.

Furthermore, existing literature indicates that MOTS-c can reduce insulin resistance and enhance GLUT4 uptake in muscle tissue. This peptide is primarily employed for weight management, as it regulates both muscle and fat metabolism, and for boosting energy levels to support cell survival in adverse conditions. MOTS-c is consistently favored by athletes aiming to enhance their performance and exhibits potential for extending longevity. Notably, the Japanese population, known for its exceptional longevity, has shown a compelling connection between MOTS-c and a prolonged lifespan, both in terms of phenotypic expression and biological mechanisms.

Various research investigations have delved into the potential therapeutic uses of MOTS-c across a spectrum of health conditions:

Metabolic Disorders: MOTS-c's capacity to enhance insulin sensitivity and ameliorate glucose metabolism offers promising avenues for addressing metabolic disorders. Studies suggest its potential in mitigating the underlying pathophysiological processes associated with conditions like type 2 diabetes and obesity.
Health Issues Related to Aging: Age-related ailments are often linked to mitochondrial dysfunction and oxidative stress. MOTS-c's ability to uphold mitochondrial integrity is proposed to offer benefits in alleviating age-related health challenges, including neurodegenerative disorders and cardiovascular diseases.
Enhancing Exercise Performance: Scientific inquiries propose that MOTS-c might elevate exercise performance and facilitate recovery by optimizing muscle function and reducing the oxidative stress induced by physical activity. This makes MOTS-c particularly relevant to athletes and individuals aiming to maximize their physical capabilities.
Neuroprotection: MOTS-c's potential for neuroprotection has come under scrutiny. By regulating cellular stress responses and preserving mitochondrial health, MOTS-c shows promise in safeguarding neurons from harm, with potential implications for neurodegenerative conditions such as Alzheimer's disease.
Anti-Inflammatory Characteristics: Chronic inflammation is a common thread in numerous health conditions. Research indicates that MOTS-c may possess anti-inflammatory properties by regulating inflammatory responses, offering therapeutic potential for disorders characterized by persistent inflammation.

Research Example #1: **The Mitochondrial-Derived Peptide MOTS-c Promotes Metabolic Homeostasis and Reduces Obesity and Insulin Resistance**

Short Summary

Mitochondria are well-recognized as functional organelles, but their role as signaling units is gaining increased recognition. The discovery of a short open reading frame (sORF) in the mitochondrial DNA (mtDNA) that encodes a signaling peptide called humanin suggests the potential presence of additional sORFs within the mtDNA. In this context, we present the identification of an sORF within the mitochondrial 12S rRNA, which codes for a 16-amino-acid peptide known as MOTS-c (mitochondrial open reading frame of the 12S rRNA-c). MOTS-c plays a pivotal role in regulating insulin sensitivity and metabolic balance. Its primary target tissue seems to be skeletal muscle, where it acts to inhibit the folate cycle and the associated de novo purine biosynthesis, ultimately leading to the activation of AMPK.

When administered to mice, MOTS-c has demonstrated the ability to prevent age-related and diet-induced insulin resistance, as well as diet-induced obesity. These findings imply that mitochondria may actively modulate metabolic equilibrium at both the cellular and organismal levels through peptides encoded within their genome.

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Highlights of This Paper MOTS-c is a 16-Amino-Acid Peptide Encoded in the Mitochondrial Genome:

MOTS-c, or mitochondrial open reading frame of the 12S rRNA type-c, is a compact, 16-amino-acid peptide encoded within the mitochondrial genome. This unique peptide is transcribed and translated from a short open reading frame (sORF) located in the 12S rRNA region of the mitochondrial DNA (mtDNA). Unlike most mitochondrial genes that utilize a mitochondria-specific genetic code, MOTS-c translation occurs in the cytoplasm, following the standard genetic code. This distinctive feature allows MOTS-c to interact with and regulate processes beyond the mitochondria. Its compact size and mitochondrial origin make it an intriguing bioactive molecule with the potential to impact cellular and organismal health.

MOTS-c Targets Muscle and Regulates Metabolism via the Folate-Purine-AMPK Pathway:

MOTS-c predominantly exerts its effects in skeletal muscle, positioning it as a key player in regulating metabolic processes within this tissue. Through a complex pathway, MOTS-c influences metabolism via the folate-purine-AMPK pathway. This pathway involves the inhibition of the folate cycle and the associated de novo purine biosynthesis, which ultimately leads to the activation of AMP-activated protein kinase (AMPK). AMPK acts as a central cellular energy sensor by monitoring the ratio of adenosine monophosphate (AMP) to adenosine triphosphate (ATP). Activation of AMPK results in the initiation of catabolic processes aimed at generating more ATP when there is an energy deficit.

MOTS-c Mediates Mitochondrial Regulation of Insulin and Metabolic Homeostasis:

MOTS-c plays a pivotal role in mediating mitochondrial regulation of insulin sensitivity and overall metabolic homeostasis. It acts as a signaling peptide that communicates between the mitochondria and the cell nucleus. When cells are exposed to metabolic stress or other perturbations, MOTS-c translocates into the nucleus, where it directly influences the expression of nuclear genes related to adaptive metabolic responses. This coordination between the mitochondria and the nucleus helps fine-tune the cellular response to changing energy demands.

MOTS-c Protects Against Age- and Diet-Dependent Insulin Resistance and Obesity:

One of the most intriguing aspects of MOTS-c is its potential to protect against age-related and diet-induced health challenges. Research suggests that MOTS-c can prevent age-dependent insulin resistance, which is a common feature of aging and a precursor to metabolic disorders such as type 2 diabetes. Additionally, MOTS-c has been shown to mitigate diet-induced insulin resistance and obesity, providing a promising avenue for addressing the global epidemic of obesity and its related health complications. By maintaining insulin sensitivity and promoting healthy metabolism, MOTS-c has the potential to improve the overall metabolic health of individuals, helping to prevent or manage conditions associated with insulin resistance and obesity.

Summary: Identification of a Novel Expressed sORFEncoded within the Mitochondrial Genome

Previously, studies have identified cDNAs originating from the 12S rRNA region in human myeloblasts after interferon stimulation, but the precise sequences remained unknown (Tsuzuki et al., 1983). An in-depth computational search for potential short open reading frames (sORFs) within the human 12S rRNA led to the discovery of one sORF consisting of 51 base pairs with a robust Kozak sequence (Harhay et al., 2005). This sequence translates into a 16-amino-acid peptide, subject to various post-translational modifications (Figures 1A, S1A, and S1B). Researchers have termed this peptide MOTS-c, which stands for mitochondrial open reading frame of the 12S rRNA type-c. MOTS-c peptide translation is performed in the cytoplasm, utilizing the standard genetic code, as opposed to mitochondrial translation, which employs a mitochondria-specific genetic code resulting in the generation of start and stop codons (Figure 1A). This suggests that its polyadenylated transcript (Figure 1B) is exported from the mitochondria. The export mechanism of mitochondrial RNAs, including tRNA and rRNA, is still not well understood (Amikura et al., 2001; Attardi and Attardi, 1968; Kashikawa et al., 1999, 2001; Kobayashi et al., 1993, 1998; Maniataki and Mourelatos, 2005; Nakamura et al., 1996).

A comparative analysis of MOTS-c's peptide sequence alignment among 14 different species and their deduced phylogenetic trees revealed a high degree of conservation, particularly in the first 11 residues (Figures 1C and 1D). To explore whether these 11 amino acids have evolved due to positive selection, researchers calculated the ratios of non-synonymous (dN) to synonymous substitutions (dS) for each residue across the 14 species. This analysis identified four residues that were significantly undergoing positive selection (dN/dS > 1) at positions 4 (Q), 5 (E), 7 (G), and 9 (I), and two residues that were undergoing purifying selection (dN/dS < 1) at positions 3 (W) and 10 (F) (Figure 1E). Positive selection was also confirmed using random effects likelihood (REL) analysis with a posterior probability greater than 0.95 and a Bayes factor greater than 50 (Figure S1C) (Kosakovsky Pond and Frost, 2005). All subsequent investigations were based on the human MOTS-c sequence.

They considered the possibility that MOTS-c might also have a nuclear origin due to a phenomenon known as nuclear mtDNA transfer (NUMT) (Ricchetti et al., 2004). However, a search using the NCBI nucleotide basic local alignment search tool (BLASTN) found that none of the putative NUMT-derived peptides shared complete homology with mitochondrial-encoded MOTS-c (Figure S1D). Furthermore, a BLAST search using the human expression sequence tag (EST) database revealed 101 hits whose mRNA sequences were entirely homologous to the mitochondrial 12S rRNA locus (Table S1). Interestingly, rats (Rattus norvegicus) lack NUMT sequences for MOTS-c, indicating that mitochondrial DNA is its exclusive source. To further confirm MOTS-c's mitochondrial origin in humans, we selectively depleted mitochondrial DNA in HeLa cells (HeLa-r0) and observed the elimination of both 12S rRNA and MOTS-c transcripts (Figure 1F). HeLa-r0 cells exhibited undetectable levels of mitochondrial-encoded cytochrome oxidase I and II (MT-COI/II) and MOTS-c, as determined using specific MOTS-c antibodies (Figure S1E). However, nuclear-encoded GAPDH expression remained unaltered (Figure 1G). HeLa and HEK293 cells displayed a degree of mitochondrial co-localization (Figures 1H, 1I, and S1F), while HeLa-r0 cells exhibited a loss of MOTS-c expression and mitochondrial co-localization (Figure 1H).

Moreover, they also selectively depleted mitochondrial RNA using actinonin (Richter et al., 2013) and observed a time-dependent loss of both MOTS-c and MT-COI expression (Figures 1J and S1H). Thus, using the r0 system and actinonin, Researchers provide evidence for MOTS-c's mitochondrial origin at both the DNA and RNA levels. MOTS-c was detected in various tissues in mice and rats (Figure 1K) as well as in circulation in human and rodent plasma, as determined using a MOTS-c-specific ELISA (Figures 1L, S1G, and S1H). Once again, the absence of NUMTs in rats implies that mitochondrial DNA is the sole source of MOTS-c. Notably, fasting lowered the endogenous expression of MOTS-c in certain metabolically active and mitochondria-rich tissues (skeletal muscle and testes), as well as in plasma, while homeostatic tissues (such as brain and heart) exhibited sustained levels (Figures 1M and 1N).

“Figure 1. Identification of a Novel Expressed sORF Encoded within the Mitochondrial Genome (A) MOTS-c is encoded as a 51-bp short open reading frame (sORF) in the mitochondrial 12S rRNA. The mitochondrial genetic code yields tandem start/stop codons, while the cytoplasmic genetic code generates a viable peptide. (B) 3' rapid amplification of cDNA ends (3'RACE) of polyadenylated MOTS-c and humanin transcripts. (C–E) Phylogenetic analysis of MOTS-c with (C) multiple peptide sequence alignment in 14 species, (D) its phylogenetic tree and branch length (estimated number of substitutions per site), (E) the rate of non-synonymous (dN) and synonymous (dS) substitutions, and their ratio (dN/dS) for the first well-conserved 11 residues of MOTS-c. The red bars represent residues that evolved under significant positive selection, and the gray bars represent those under significant purifying selection. (F–H) HeLa-r0 cells are devoid of mitochondrial DNA. HeLa cells versus HeLa-r0 cells: (F) 12S rRNA and MOTS-c transcripts by qRT-PCR, (G) MOTS-c peptide and mitochondrial-encoded cytochrome C oxidase I and II (MT-COI/II) protein, and nuclear-encoded GAPDH by immunoblotting, (H) MOTS-c (green), mitochondrial resident HSP60 (red), and nucleus (blue) by immunocytochemistry (ICC). Scale bar, 100 mm. (I) MOTS-c (green), HSP60 (red), and nucleus (blue) immunostaining in HEK293 cells. Scale bar, 20 mm. (J) Time-course detection of MOTS-c and MT-COI after treating with actinonin (150 mM), which causes mitochondrial RNA degradation. (K and L) MOTS-c is detected in (K) various tissues in mice and rats and (L) circulation (plasma) in humans and rodents. (M and N) Fasting alters expression of endogenous MOTS-c in (M) tissues and (N) plasma in mice. Data shown as mean ± SEM. Student's t-test. p<0.05, p<0.01, p<0.001. See also Figure S1 and Table S1 for additional information on MOTS-c and validation for Western blotting, ICC, and ELISA.”

This had a marked impact on the expression of genes associated with cellular metabolism and inflammation (Figure 2D; Table S2). Given the central role of mitochondria in metabolic processes, they further examined the effect of MOTS-c on cellular metabolism using an unbiased global metabolomic profiling approach in vitro. Researchers employed a "gain-of-function" model using HEK293 cells, which were either stably overexpressing MOTS-c (MOTS-c-ST) or treated exogenously with synthetic MOTS-c (10mM) for 24 and 72 hours. Out of the 356 named metabolites, 194 exhibited significant alterations in MOTS-c-ST cells, with 49 and 177 showing significant changes after 24 and 72 hours, respectively (Figure 2E). The pattern of metabolites also evolved over time, with most biochemicals remaining consistently altered at both 24 and 72 hours (Figure 2F). The majority of metabolites altered in MOTS-c-ST cells overlapped with those in cells treated with MOTS-c for 72 hours (Figure 2F). There were metabolites consistently changed in all three groups, with those involved in purine metabolism and dipeptide metabolism being consistently reduced, while those related to acylcarnitine metabolism and the methionine cycle were significantly increased (Figure 2G).

“Figure 2. MOTS-c Is a Bioactive Peptide that Regulates Gene Expression and Cellular Metabolism (A–D) Microarray analysis on HEK293 cells treated with MOTS-c (10mM) for 4 and 72 hours (n=6). (A) Principal component analysis (PCA). (B) Parametric analysis of gene set enrichment (PAGE) relative to control cells at the same time point. (C) Venn diagram depicting upregulated (red) and downregulated (blue) genes per time point. (D) Gene ontology analysis on HEK293 cells treated with MOTS-c for 72 hours. (E–G) Global unbiased metabolomics on HEK293 cells treated with MOTS-c (10mM) for 24 and 72 hours or stably transfected with MOTS-c (MOTS-c-ST) or empty vector (EV-ST) (n=5). Welch's two-sample t-test. (E) Total number of significantly or near-significantly changed metabolites. (F) Venn diagram depicting upregulated (red) and downregulated (blue) metabolites in MOTS-c-ST cells and HEK293 cells treated with MOTS-c for 24 and 72 hours compared to their controls. (G) List of metabolites that were consistently altered in all three groups. See also Table S2.”

Research Example #3: **MOTS-c reduces myostatin and muscle atrophy signaling**

Summary

Obesity and type 2 diabetes are metabolic disorders often linked to sarcopenia and muscle dysfunction. MOTS-c, a peptide derived from the mitochondria, functions as a systemic hormone and plays a role in maintaining metabolic balance. While it's known that MOTS-c enhances insulin sensitivity in skeletal muscle, its impact on muscle atrophy hasn't been explored. Myostatin, a protein that negatively regulates skeletal muscle mass, is a potential contributor to muscle wasting induced by insulin resistance.

Remarkably, our investigation revealed an inverse relationship between MOTS-c levels in the bloodstream and myostatin levels in human subjects. Furthermore, researchers demonstrated that MOTS-c effectively prevents palmitic acid-induced muscle atrophy in differentiated C2C12 myotubes. When administered, MOTS-c led to a reduction in myostatin levels in the plasma of diet-induced obese mice. This outcome can be attributed to MOTS-c's ability to enhance AKT phosphorylation, which, in turn, inhibits a crucial transcription factor, FOXO1, responsible for activating myostatin and other genes associated with muscle wasting. MOTS-c achieves this by promoting mTORC2 activity and inhibiting PTEN, thereby modulating AKT phosphorylation. Going further upstream, MOTS-c also stimulates CK2 activity, which subsequently results in PTEN inhibition.

These findings suggest that by curtailing myostatin's actions, MOTS-c holds promise as a potential therapy for insulin resistance-related skeletal muscle atrophy, as well as other conditions characterized by muscle wasting, including sarcopenia.

It's worth noting that MOTS-c, a mitochondria-derived peptide, exhibits the remarkable ability to reduce the signaling pathways associated with high-fat-diet-induced muscle atrophy by diminishing myostatin expression. The CK2-PTEN-mTORC2-AKT-FOXO1 pathways are pivotal in elucidating how MOTS-c exerts its influence on myostatin expression.

Highlights from this paper include:

1. Plasma MOTS-c Levels Are Inversely Correlated with Plasma Myostatin Levels in Human

Plasma mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c) levels are inversely correlated with plasma myostatin levels in human. Correlations between plasma myostatin levels and plasma MOTS-c levels in Japanese male subjects without a medical history of type 2 diabetes, myocardial infarction, or hypertension. The Spearman’s correlation coefficients were applied for the statistical analyses.

MOTS-c Prevents Palmitic Acid-Induced Atrophy in Differentiated C2C12 Myotubes

3.MOTS-c Decreases Myostatin Levels in Plasma and Skeletal Muscle from Diet-Induced Obese Mice

Mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c) decreases myostatin levels in high-fat-diet-fed mice. C57BL/6J mice fed a high-fat diet were injected with MOTS-c peptide (5 mg/kg; ip) for 8 wk. Plasma myostatin levels (A) were measured by ELISA, whereas the myostatin mRNA expression (B) in skeletal muscle was measured by qRT-PCR. Data are reported as means ± SE of 7 or 12 mice per group. Significant differences were determined by Student’s t tests. *P < 0.05 and **P < 0.01.

MOTS-c Inhibits FOXO1 Transcription Activity in Skeletal Muscle from Diet-Induced Obese Mice

MOTS-c Increases AKT Phosphorylation and mTOR Complex 2 Activity

MOTS-c Reduces Phosphatase and Tensin Homolog (PTEN) Activity in Skeletal Muscle from Diet-Induced Obese Mice

MOTS-c Prevents Muscle Atrophy in Short-Term Diet-Induced Obese Mice

“Mitochondrial open reading frame of the 12S ribosomal RNA type-c (MOTS-c) prevents muscle atrophy in mice fed a high-fat diet. CD-1 mice fed either normal diet (ND) or high-fat diet (HFD) were injected with the MOTS-c peptide (0.5 mg/kg/day ip) for 3 wk. Body weight (A), abdominal fat (B), and total mass (mg) (C) of gastrocnemius, soleus, and plantaris muscle per bodyweight (mg/g) were measured. D: myostatin mRNA expression in skeletal muscle was measured by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). E: the correlation between myostatin mRNA expression and muscle mass/body weight (BW). The data are reported as means ± SE of mice per group. Normal diet group, n = 6; high-fat-diet group, n = 10. Significant differences were determined by one-way ANOVA followed by Tukey’s post hoc test. *P < 0.05 and **P < 0.01. The Spearman’s correlation coefficients were applied for the statistical analyses of E.”

Research Example #3: The mitochondrial signaling peptide MOTS-c improves myocardial performance during exercise training in rats

The consensus in the medical community strongly supports the idea that regular physical activity holds significant advantages for cardiovascular health. Engaging in frequent exercise is robustly linked to a reduction in cardiovascular mortality and the risk of developing cardiovascular disease (CVD).

Individuals who maintain an active lifestyle tend to exhibit lower blood pressure, increased insulin sensitivity, and a more favorable profile of plasma lipoproteins. Studies on animal exercise models have demonstrated that repetitive physical activity can hinder the formation of atherogenesis and boost the presence of vasodilatory agents like nitric oxide. Furthermore, exercise has been found to have positive impacts on the heart. In the short term, it results in an increase in cardiac output and blood pressure. However, individuals who have adapted to regular exercise show a lower resting heart rate and experience cardiac hypertrophy.

MOTS-c, short for "mitochondrial ORF of the 12S rRNA type-c," is a mitochondrial-derived peptide (MDP) that contributes to the maintenance of metabolic balance. It accomplishes this, in part, by engaging with AMPK and directly influencing adaptive nuclear gene expression once it relocates to the cell nucleus. The presence of MOTS-c varies with age and can be found in multiple tissues, including skeletal muscle and in the bloodstream, leading to its characterization as a "mitochondrial hormone" or "mitokine."

While most studies have focused on the cardiovascular effects of MOTS-c, such as its impact on coronary endothelial dysfunction and pathological changes in heart muscle, little is known about how MOTS-c interacts with aerobic exercise and its influence on healthy changes in heart structure.

In a recent study, researchers investigated the effects of MOTS-c on both the function (monitored using Millar carotid catheter) and structure (evaluated through hematoxylin–eosin staining, transmission electron microscopy, and echocardiography) of the heart in rats subjected to chronic aerobic exercise. They also explored whether MOTS-c could enhance the normal adaptations of the heart to exercise training. These findings provide experimental support for the potential use of 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 injected with MOTS-c and saline half an hour before the start of the exercise protocol. Rats in the ME group were injected 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. 1 A). 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. 1 B). 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. 1 C).”

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 injection 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. 2 A,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 includes 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 injection 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 injection 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).

Exogenous injection of MOTS-c during exercise can increase the endogenous MOTS-c of the myocardium and activate AMPK

“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 injected 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.”

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