Mitochondrial-derived microprotein MOTS-c attenuates immobilization-induced skeletal muscle atrophy by suppressing lipid infiltration

Lu P., Li X., Li B., Li X., Wang C., Liu Z., Ji Y., Wang X., Wen Z., Fan J., Yi C., Song M., Wang X.

Acute lung injury (ALI) is a life-threatening complication of cardiac surgery that has a high rate of morbidity and mortality. Epithelial ferroptosis is believed to be involved in the pathogenesis of ALI. MOTS-c has been reported to play a role in regulating inflammation and sepsis-associated ALI. The purpose of this study is to observe the effect of MOTS-c on myocardial ischemia reperfusion (MIR)-induced ALI and ferroptosis. In humans, we used ELISA kits to investigate MOTS-c and malondialdehyde (MDA) levels in patients undergoing off-pump coronary artery bypass grafting (CABG). In vivo, we pretreated Sprague-Dawley rats with MOTS-c, Ferrostatin-1 and Fe-citrate(Ⅲ). We conducted Hematoxylin and Eosin (H&E) staining and detection of ferroptosis-related genes in MIR-induced ALI rats. In vitro, we evaluated the effect of MOTS-c on hypoxia regeneration (HR)-induced mouse lung epithelial-12 (MLE-12) ferroptosis and analyzed the expression of PPARγ through western blotting. We found that circulating MOTS-c levels were decreased in postoperative ALI patients after off-pump CABG, and that ferroptosis contributed to ALI induced by MIR in rats. MOTS-c suppressed ferroptosis and alleviated ALI induced by MIR, and the protective effect of MOTS-c- was dependent on PPARγ signaling pathway. Additionally, HR promoted ferroptosis in MLE-12 cells, and MOTS-c inhibited ferroptosis against HR through the PPARγ signaling pathway. These findings highlight the therapeutic potential of MOTS-c for improving postoperative ALI induced by cardiac surgery.

Kumagai H., Miller B., Kim S., Leelaprachakul N., Kikuchi N., Yen K., Cohen P.

Sports genetics research began in the late 1990s and over 200 variants have been reported as athletic performance- and sports injuries-related genetic polymorphisms. Genetic polymorphisms in the α-actinin-3 (ACTN3) and angiotensin-converting enzyme (ACE) genes are well-established for athletic performance, while collagen-, inflammation-, and estrogen-related genetic polymorphisms are reported as genetic markers for sports injuries. Although the Human Genome Project was completed in the early 2000s, recent studies have discovered previously unannotated microproteins encoded in small open reading frames. Mitochondrial microproteins (also called mitochondrial-derived peptides) are encoded in the mtDNA, and ten mitochondrial microproteins, such as humanin, MOTS-c (mitochondrial ORF of the 12S rRNA type-c), SHLPs 1–6 (small humanin-like peptides 1 to 6), SHMOOSE (Small Human Mitochondrial ORF Over SErine tRNA), and Gau (gene antisense ubiquitous in mtDNAs) have been identified to date. Some of those microproteins have crucial roles in human biology by regulating mitochondrial function, and those, including those to be discovered in the future, could contribute to a better understanding of human biology. This review describes a basic concept of mitochondrial microproteins and discusses recent findings about the potential roles of mitochondrial microproteins in athletic performance as well as age-related diseases.

Hyatt J.K.

Skeletal muscle adapts to aerobic exercise training, in part, through fast-to-slow phenotypic shifts and an expansion of mitochondrial networks. Recent research suggests that the local and systemic benefits of exercise training also may be modulated by the mitochondrial-derived peptide, MOTS-c. Using a combination of acute and chronic exercise challenges, the goal of the present study was to characterize the interrelationship between MOTS-c and exercise. Compared to sedentary controls, 4-8 weeks of voluntary running increased MOTS-c protein expression ~1.5-5-fold in rodent plantaris, medial gastrocnemius, and tibialis anterior muscles and is sustained for 4-6 weeks of detraining. This MOTS-c increase coincides with elevations in mtDNA reflecting an expansion of the mitochondrial genome to aerobic training. In a second experiment, a single dose (15 mg/kg) of MOTS-c administered to untrained mice improved total running time (12% increase) and distance (15% increase) during an acute exercise test. In a final experiment, MOTS-c protein translocated from the cytoplasm into the nucleus in two of six mouse soleus muscles 1 h following a 90-min downhill running challenge; no nuclear translocation was observed in the plantaris muscles from the same animals. These findings indicate that MOTS-c protein accumulates within trained skeletal muscle likely through a concomitant increase in mtDNA. Furthermore, these data suggest that the systemic benefits of exercise are, in part, mediated by an expansion of the skeletal muscle-derived MOTS-c protein pool. The benefits of training may persist into a period of inactivity (e.g., detraining) resulting from a sustained increase in intramuscular MOTS-c proteins levels.

Yang T., Luo K., Deng X., Xu L., Wang R., Ji P.

While emergency laparotomy has been associated with high rates of postoperative mortality and adverse events, preoperative systematic evaluation of patients may improve perioperative outcomes. However, due to the critical condition of the patient and the limited operation time, it is challenging to conduct a comprehensive evaluation. In recent years, sarcopenia is considered a health problem associated with an increased incidence of poor prognosis. This study aimed to investigate the effect of sarcopenia on 30-day mortality and postoperative adverse events in patients undergoing emergency laparotomy. We systematically searched databases including PubMed, Embase, and Cochrane for all studies comparing emergency laparotomy in patients with and without sarcopenia up to March 1, 2022. The primary outcome was of 30-day postoperative mortality. Secondary outcomes were the length of hospital stay, the incidence of adverse events, number of postoperative intensive care unit (ICU) admissions, and ICU length of stay. Study and outcome-specific risk of bias were assessed using the Quality in Prognosis Studies (QUIPS) tool. We rated the certainty of evidence using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE). A total of 11 eligible studies were included in this study. The results showed that patients with sarcopenia had a higher risk of death 30 days after surgery (OR = 2.42, 95% CI = 1.93–3.05, P < 0.00001). More patients were admitted to ICU after surgery (OR = 1.58, 95% CI = 1.11–2.25, P = 0.01). Both the ICU length of stay (MD = 0.55, 95% CI = 0.05–1.06, P = 0.03) and hospital length of stay (MD = 2.33, 95% CI = 1.33–3.32, P < 0.00001) were longer in the sarcopenia group. The incidence of postoperative complications was also significantly higher in patients with sarcopenia (OR = 1.78, 95% CI = 1.41–2.26, P < 0.00001). In emergency laparotomy, sarcopenia was associated with increased 30-day postoperative mortality. Both the lengths of stay in the ICU and the total length of hospital stay were significantly higher than those in non-sarcopenic patients. Therefore, we concluded that sarcopenia can be used as a tool to identify preoperative high-risk patients, which can be considered to develop new postoperative risk prediction models. Registration number Registered on Prospero with the registration number of CRD42022300132.

Miller B., Kim S., Kumagai H., Yen K., Cohen P.

The mechanisms that explain mitochondrial dysfunction in aging and healthspan continue to be studied, but one element has been unexplored: microproteins. Small open reading frames in circular mitochondria DNA can encode multiple microproteins, called mitochondria-derived peptides (MDPs). Currently, eight MDPs have been published: humanin, MOTS-c, and SHLPs 1–6. This Review describes recent advances in microprotein discovery with a focus on MDPs. It discusses what is currently known about MDPs in aging and how this new understanding could add to the way we understand age-related diseases including type 2 diabetes, cancer, and neurodegenerative diseases at the genomic, proteomic, and drug-development levels.

Kumagai H., Natsume T., Kim S., Tobina T., Miyamoto-Mikami E., Shiose K., Ichinoseki-Sekine N., Kakigi R., Tsuzuki T., Miller B., Yen K., Murakami H., Miyachi M., Zempo H., Dobashi S., et. al.

Human skeletal muscle fiber is heterogenous due to its diversity of slow- and fast-twitch fibers. In human, slow-twitched fiber gene expression is correlated to MOTS-c, a mitochondria-derived peptide that has been characterized as an exercise mimetic. Within the MOTS-c open reading frame, there is an East Asian-specific m.1382A>C polymorphism (rs111033358) that changes the 14th amino acid of MOTS-c (i.e., K14Q), a variant of MOTS-c that has less biological activity. Here, we examined the influence of the m.1382A>C polymorphism causing MOTS-c K14Q on skeletal muscle fiber composition and physical performance. The myosin heavy chain (MHC) isoforms (MHC-I, MHC-IIa, and MHC-IIx) as an indicator of muscle fiber composition were assessed in 211 Japanese healthy individuals (102 men and 109 women). Muscular strength was measured in 86 physically active young Japanese men by using an isokinetic dynamometer. The allele frequency of the m.1382A>C polymorphism was assessed in 721 Japanese athletes and 873 ethnicity-matched controls. The m.1382A>C polymorphism genotype was analyzed by TaqMan SNP Genotyping Assay. Individuals with the C allele of the m.1382A>C exhibited a higher proportion of MHC-IIx, an index of fast-twitched fiber, than the A allele carriers. Men with the C allele of m.1382A>C exhibited significantly higher peak torques of leg flexion and extension. Furthermore, the C allele frequency was higher in the order of sprint/power athletes (6.5%), controls (5.1%), and endurance athletes (2.9%). Additionally, young male mice were injected with the MOTS-c neutralizing antibody once a week for four weeks to mimic the C allele of the m.1382A>C and assessed for protein expression levels of MHC-fast and MHC-slow. Mice injected with MOTS-c neutralizing antibody showed a higher expression of MHC-fast than the control mice. These results suggest that the C allele of the East Asian-specific m.1382A>C polymorphism leads to the MOTS-c K14Q contributes to the sprint/power performance through regulating skeletal muscle fiber composition.

Qualls A.E., Southern W.M., Call J.A.

Skeletal muscle mitochondria are highly adaptable, highly dynamic organelles that maintain the functional integrity of the muscle fiber by providing ATP for contraction and cellular homeostasis (e.g., Na+/K+ ATPase). Emerging as early modulators of inflammation, mitochondria sense and respond to cellular stress. Mitochondria communicate with the environment, in part, by release of physical signals called mitochondrial-derived damage-associated molecular patterns (mito-DAMPs) and deviation from routine function (e.g., reduced ATP production, Ca2+ overload). When skeletal muscle is compromised, mitochondria contribute to an acute inflammatory response necessary for myofibril regeneration; however, exhaustive signaling associated with altered or reduced mitochondrial function can be detrimental to muscle outcomes. Here, we describe changes in mitochondrial content, structure, and function following skeletal muscle injury and disuse and highlight the influence of mitochondria-cytokine crosstalk on muscle regeneration and recovery. Although the appropriate therapeutic modulation following muscle stressors remains unknown, retrospective gene expression analysis reveals that interleukin-6 (IL-6), interleukin-1β (IL-1β), chemokine C-X-C motif ligand 1 (CXCL1), and monocyte chemoattractant protein 1 (MCP-1) are significantly upregulated following three unique muscle injuries. These cytokines modulate mitochondrial function and execute bona fide pleiotropic roles that can aid functional recovery of muscle, however, when aberrant, chronically disrupt healing partly by exacerbating mitochondrial dysfunction. Multidisciplinary efforts to delineate the opposing regulatory roles of inflammatory cytokines in the muscle mitochondrial environment are required to modulate regenerative behavior following skeletal muscle injury or disuse. Future therapeutic directions to consider include quenching or limited release of mito-DAMPs and cytokines present in cytosol or circulation.

Kumagai H., Coelho A.R., Wan J., Mehta H.H., Yen K., Huang A., Zempo H., Fuku N., Maeda S., Oliveira P.J., Cohen P., Kim S.

MOTS-c, a mitochondrial-derived peptide reduces high-fat-diet-induced muscle atrophy signaling by reducing myostatin expression. The CK2-PTEN-mTORC2-AKT-FOXO1 pathways play key roles in MOTS-c action on myostatin expression.

Reynolds J.C., Lai R.W., Woodhead J.S., Joly J.H., Mitchell C.J., Cameron-Smith D., Lu R., Cohen P., Graham N.A., Benayoun B.A., Merry T.L., Lee C.

Healthy aging can be promoted by enhanced metabolic fitness and physical capacity. Mitochondria are chief metabolic organelles with strong implications in aging that also coordinate broad physiological functions, in part, using peptides that are encoded within their independent genome. However, mitochondrial-encoded factors that actively regulate aging are unknown. Here, we report that mitochondrial-encoded MOTS-c can significantly enhance physical performance in young (2 mo.), middle-age (12 mo.), and old (22 mo.) mice. MOTS-c can regulate (i) nuclear genes, including those related to metabolism and proteostasis, (ii) skeletal muscle metabolism, and (iii) myoblast adaptation to metabolic stress. We provide evidence that late-life (23.5 mo.) initiated intermittent MOTS-c treatment (3x/week) can increase physical capacity and healthspan in mice. In humans, exercise induces endogenous MOTS-c expression in skeletal muscle and in circulation. Our data indicate that aging is regulated by genes encoded in both of our co-evolved mitochondrial and nuclear genomes. Exercise has beneficial effects on metabolism and overall physiologic fitness in aged organisms. Here the authors show that MOTS-c is a mitochondrial-encoded exercise-induced peptide that regulates skeletal muscle metabolism and improves healthspan of older mice.

Zempo H., Kim S., Fuku N., Nishida Y., Higaki Y., Wan J., Yen K., Miller B., Vicinanza R., Miyamoto-Mikami E., Kumagai H., Naito H., Xiao J., Mehta H.H., Lee C., et. al.

Type 2 Diabetes (T2D) is an emerging public health problem in Asia. Although ethnic specific mtDNA polymorphisms have been shown to contribute to T2D risk, the functional effects of the mtDNA polymorphisms and the therapeutic potential of mitochondrial-derived peptides at the mtDNA polymorphisms are underexplored. Here, we showed an Asian-specific mitochondrial DNA variation m.1382A>C (rs111033358) leads to a K14Q amino acid replacement in MOTS-c, an insulin sensitizing mitochondrial-derived peptide. Meta-analysis of three cohorts (n = 27,527, J-MICC, MEC, and TMM) show that males but not females with the C-allele exhibit a higher prevalence of T2D. In J-MICC, only males with the C-allele in the lowest tertile of physical activity increased their prevalence of T2D, demonstrating a kinesio-genomic interaction. High-fat fed, male mice injected with MOTS-c showed reduced weight and improved glucose tolerance, but not K14Q-MOTS-c treated mice. Like the human data, female mice were unaffected. Mechanistically, K14Q-MOTS-c leads to diminished insulin-sensitization in vitro. Thus, the m.1382A>C polymorphism is associated with susceptibility to T2D in men, possibly interacting with exercise, and contributing to the risk of T2D in sedentary males by reducing the activity of MOTS-c.

Merry T.L., Chan A., Woodhead J.S., Reynolds J.C., Kumagai H., Kim S., Lee C.

Mitochondrial-derived peptides (MDPs) are small bioactive peptides encoded by short open-reading frames (sORF) in mitochondrial DNA that do not necessarily have traditional hallmarks of protein-coding genes. To date, eight MDPs have been identified, all of which have been shown to have various cyto- or metaboloprotective properties. The 12S ribosomal RNA ( MT-RNR1) gene harbors the sequence for MOTS-c, whereas the other seven MDPs [humanin and small humanin-like peptides (SHLP) 1–6] are encoded by the 16S ribosomal RNA gene. Here, we review the evidence that endogenous MDPs are sensitive to changes in metabolism, showing that metabolic conditions like obesity, diabetes, and aging are associated with lower circulating MDPs, whereas in humans muscle MDP expression is upregulated in response to stress that perturbs the mitochondria like exercise, some mtDNA mutation-associated diseases, and healthy aging, which potentially suggests a tissue-specific response aimed at restoring cellular or mitochondrial homeostasis. Consistent with this, treatment of rodents with humanin, MOTS-c, and SHLP2 can enhance insulin sensitivity and offer protection against a range of age-associated metabolic disorders. Furthermore, assessing how mtDNA variants alter the functions of MDPs is beginning to provide evidence that MDPs are metabolic signal transducers in humans. Taken together, MDPs appear to form an important aspect of a retrograde signaling network that communicates mitochondrial status with the wider cell and to distal tissues to modulate adaptative responses to metabolic stress. It remains to be fully determined whether the metaboloprotective properties of MDPs can be harnessed into therapies for metabolic disease.

Kim S., Miller B., Kumagai H., Silverstein A.R., Flores M., Yen K.

A decline in mitochondrial quality and activity has been associated with normal aging and correlated with the development of a wide range of age-related diseases. Here, we review the evidence that a decline in the levels of mitochondrial-derived peptides contributes to aging and age-related diseases. In particular, we discuss how mitochondrial-derived peptides, humanin and MOTS-c, contribute to specific aspects of the aging process, including cellular senescence, chronic inflammation, and cognitive decline. Genetic variations in the coding region of humanin and MOTS-c that are associated with age-related diseases are also reviewed, with particular emphasis placed on how mitochondrial variants might, in turn, regulate MDP expression and age-related phenotypes. Taken together, these observations suggest that mitochondrial-derived peptides influence or regulate a number of key aspects of aging and that strategies directed at increasing mitochondrial-derived peptide levels might have broad beneficial effects.

Miller B., Kim S., Kumagai H., Mehta H.H., Xiang W., Liu J., Yen K., Cohen P.

Mitochondrial-derived peptides (MDPs) are a novel class of bioactive microproteins that modify cell metabolism. The the eight MDPs that been characterized (e.g., humanin, MOTS-c, SHLPs1-6) attenuate disease pathology including Alzheimer's disease, prostate cancer, macular degeneration, cardiovascular disease, and diabetes. The association between disease and human genetic variation in MDPs is underexplored, although two polymorphisms in humanin and MOTS-c associate with cognitive decline and diabetes, respectively, suggesting a precise role for MDPs in disease-modification. There could be hundreds of additional MDPs that have yet to be discovered. Altogether, MDPs could explain unanswered biological and metabolic questions and are part of a growing field of novel microproteins encoded by small open reading frames. In this review, the current state of MDPs are summarized with an emphasis on biological and therapeutic implications.

D’Souza R.F., Woodhead J.S., Hedges C.P., Zeng N., Wan J., Kumagai H., Lee C., Cohen P., Cameron-Smith D., Mitchell C.J., Merry T.L.

Mitochondria putatively regulate the aging process, in part, through the small regulatory peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c) that is encoded by the mitochondrial genome. Here we investigated the regulation of MOTS-c in the plasma and skeletal muscle of healthy aging men. Circulating MOTS-c reduced with age, but older (70-81 y) and middle-aged (45-55 y) men had ~1.5-fold higher skeletal muscle MOTS-c expression than young (18-30 y). Plasma MOTS-c levels only correlated with plasma in young men, was associated with markers of slow-type muscle, and associated with improved muscle quality in the older group (maximal leg-press load relative to thigh cross-sectional area). Using small mRNA assays we provide evidence that MOTS-c transcription may be regulated independently of the full length 12S rRNA gene in which it is encoded, and expression is not associated with antioxidant response element (ARE)-related genes as previously seen in culture. Our results suggest that plasma and muscle MOTS-c are differentially regulated with aging, and the increase in muscle MOTS-c expression with age is consistent with fast-to-slow type muscle fiber transition. Further research is required to determine the molecular targets of endogenous MOTS-c in human muscle but they may relate to factors that maintain muscle quality.

Xinqiang Y., Quan C., Yuanyuan J., Hanmei X.

MOTS-c (mitochondrial open-reading-frame of the twelve S rRNA-c), a mitochondrial-derived 16-amino acid peptide, targets the methionine-folate cycle, increases 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) levels, and eventually activates AMP-activated protein kinase (AMPK). AMPK activation can attenuate neutrophil pro-inflammatory activity and attenuates lipoteichoic acid (LTA) and lipopolysaccharide (LPS) induced acute lung injury (ALI) in mice. However, to our knowledge, the role of MOTS-c in LPS-induced ALI remains unclear. Hence, we investigated the potential effectiveness and underlying mechanism of MOTS-c against LPS-induced ALI in mice. The intraperitoneal administration of MOTS-c (5 mg/kg, i.p., bid, 6 days) before intratracheal LPS instillation attenuated body weight loss and pulmonary edema, inhibited neutrophilic tissue infiltration in lung tissue, downregulated the expression of cytokine-induced neutrophil chemoattractant-1 (CINC-1) and intercellular cell adhesion molecule-1 (ICAM-1) in lung tissues, decreased the levels of TNF-α, IL-1β, and IL-6, and increased the expression of IL-10 and SOD in serum, lung tissue, and bronchoalvelolar lavage fluid (BALF). Moreover, MOTS-c treatment significantly promoted p-AMPKα and SIRT1 expression and suppressed LPS-induced ERK, JNK, p38, p65, and STAT3 activation in the mouse lung tissues. Collectively, these findings suggest that MOTS-c plays important roles in protecting the lungs from the inflammatory effects of LPS-induced ALI. The effects of MOTS-c are probably orchestrated by activating AMPK and SIRT1, inhibiting ERK, JNK, p65, and STAT3 signaling pathways. Thus, MOTS-c appears to be a novel and promising candidate for the treatment of ALI.

Luo Z., Ji R., Ye R., Shi Y., Pang Q., Yin M.

Mohtashami Z., Schneider K., Azimi R., Atilano S., Chwa M., Kenney M.C., Singh M.K.

Zicarelli M., Greco M., Roumeliotis S., Lo Vasco M.E., Dragone F., Kourtidou C., Alekos I., Misiti R., Foti D.P., Coppolino G., Liakopoulos V., Dounousi E., Bolignano D.

Background and Objectives: Sarcopenia is exceedingly frequent in end-stage kidney disease (ESKD) patients on dialysis, including those undergoing peritoneal dialysis (PD), and is of multifactorial origin. MOTS-c is a mitochondrial-derived peptide that promotes muscle growth whose levels are unbalanced in ESKD. In this study, we evaluated MOTS-c balance and its relationship with sarcopenia risk in an ESKD-PD cohort. Materials and Methods: MOTS-c was measured in serum, urine, and dialysate samples of 32 chronic PD patients. Patients were thus screened for sarcopenia risk by the SARC-F tool, anthropometric measurements, and physical performance tests. Results: PD patients with a very high sarcopenia risk (SARC-F ≥ 2) had significantly lower serum (sMOTS-c) and higher dialysate (dMOTS-c) levels, suggesting an increased peritoneal clearance of this substance (d/s MOTS-c). sMOTS-c levels were directly correlated with muscle performance in physical tests, while an opposite relationship was found with dMOTS-c and d/sMOTS-c. ROC analyses demonstrated the diagnostic potential of MOTS-c, particularly in combination with physical and anthropometric assessments, to identify PD patients at very high risk of sarcopenia. Conclusions: Chronic PD may negatively affect MOTS-c balance, which, in turn, may contribute to enhanced sarcopenia risk. Larger studies are needed to confirm these observations and to validate the potential utility of this substance as a biomarker for improving sarcopenia risk stratification in PD patients.

Yen K., Miller B., Kumagai H., Silverstein A., Cohen P.

Vieira F.T., Cai Y., Gonzalez M.C., Goodpaster B.H., Prado C.M., Haqq A.M.

Poor muscle quality (MQ) is a hidden health condition in obesity, commonly disregarded and underdiagnosed, associated with poor health-related outcomes. This narrative review provides an in-depth exploration of MQ in obesity, including definitions, available assessment methods and challenges, pathophysiology, association with health outcomes, and potential interventions. MQ is a broad term that can include imaging, histological, functional, or metabolic assessments, evaluating beyond muscle quantity. MQ assessment is highly heterogeneous and requires further standardization. Common definitions of MQ include 1) muscle-specific strength (or functional MQ), the ratio between muscle strength and muscle quantity, and 2) muscle composition (or morphological MQ), mainly evaluating muscle fat infiltration. An individual with obesity might still have normal or higher muscle quantity despite having poor MQ, and techniques for direct measurements are needed. However, the use of body composition and physical function assessments is still limited in clinical practice. Thus, more accessible techniques for assessing strength, muscle mass, and composition should be further explored. Obesity leads to adipocyte dysfunction, generating a low-grade chronic inflammatory state, which leads to mitochondrial dysfunction. Adipocyte and mitochondrial dysfunction result in metabolic dysfunction manifesting clinically as insulin resistance, dyslipidemia, and fat infiltration into organs such as muscle, which in excess is termed myosteatosis. Myosteatosis decreases muscle cell function and insulin sensitivity, creating a vicious cycle of inflammation and metabolic derangements. Myosteatosis increases the risk of poor muscle function, systemic metabolic complications, and mortality, presenting prognostic potential. Interventions shown to improve MQ include nutrition, physical activity/exercise, pharmacology, and metabolic and bariatric surgery.

Kumagai H., Kim S., Miller B., Zempo H., Tanisawa K., Natsume T., Lee S.H., Wan J., Leelaprachakul N., Kumagai M.E., Ramirez R., Mehta H.H., Cao K., Oh T.J., Wohlschlegel J.A., et. al.