The benefits of cardiac rehabilitation (CR) have been demonstrated in patients after myocardial infarction (MI), and in patients with chronic heart failure (HF). The core components of the CR program include improvement in exercise tolerance and optimization of coronary risk factors (i.e., lipid and lipoprotein profiles, body weight, blood glucose levels, blood pressure levels, and smoking cessation). Indeed, CR has been shown to improve exercise capacity, control of cardiovascular risk factors, quality of life, hospital readmission, and mortality rates. Nonetheless, pre- and clinical CR and exercise training models are an enormous source of potential beneficial mechanisms that can be exploited for cardiac disease therapy. Consequently, in this review, we aim to explore the unique benefits of CR in HF and coronary artery disease, focusing on the epigenetic mechanisms involved and their translational relevance. These mechanisms may represent novel therapeutic targets to promote functional recovery after cardiac injury, and non-coding RNAs could be predictive biomarkers for CR success in patients.

Cardiomyocyte loss occurs in acute and chronic cardiac injury, including cardiotoxicity due to chemotherapeutics like doxorubicin, and contributes to heart failure development. There is a pressing need for cardiac-specific therapeutics that target cardiomyocyte loss, preventing chemotherapy complications without compromising chemotherapeutic efficacy.

The authors employed massively parallel combinatorial genetic screening to find microRNA (miRNA) combinations that promote cardiomyocyte survival.

CombiGEM (combinatorial genetics en masse) screening in a cardiomyocyte cell line was followed by validation in the original cell type and screening in primary cardiomyocytes. The top combination was tested in mouse and developing zebrafish models of doxorubicin cardiotoxicity. RNA sequencing provided insight into possible mechanisms.

Multiple miRNA combinations protected cardiomyocytes from doxorubicin in vitro. The most effective (miR-222+miR-455) appeared to act synergistically, and mitigated doxorubicin cardiotoxicity phenotypes in murine and zebrafish in vivo models. RNA sequencing revealed overlapping and synergistic regulation of relevant genes and biological processes in cardiomyocytes, including mitochondrial homeostasis, oxidative stress, muscle contraction, and others.

We identified miR-222 and miR-455 as a combination with potential therapeutic applications for cardioprotection. This study furthers our knowledge of the cardiac effects of miRNAs and their combinations and demonstrates the potential of CombiGEM for cardioprotective combinatorial therapeutic discovery.

Background/Objectives: High-intensity physical activity, especially in contact sports, may have harmful effect on athletes' health. The aim of the study is to determine acute changes in the function of the left ventricle in rugby players after a competitive match. Methods: A prospective, clinical, observational case-control study was conducted. All cases were European Caucasian male athletes, older than 18 years, who had played for at least 60 min in the investigated match. A transthoracic echocardiography and blood tests were performed in all the participants two days before the match and within one hour after the match. Results: The total number of examinees was 34. Out of the 31 measured echocardiographic parameters, 22 showed a statistically significant change before and after the match. We also observed changes in echocardiographic parameters in relation to the increase in high-sensitivity troponin I. Two-dimensional left ventricle (LV) end-systolic (75 ± 10.5 vs. 67.1 ± 10 mL, p = 0.032) and LV end-diastolic (149.7 ± 24.6 vs. 133.8 ± 13.3 mL, p = 0.020) volumes, 3D LV end-systolic volume (75.8 ± 9.2 vs. 67.4 ± 9.5 mL, p = 0.014), indexed 2D LV end-diastolic volume (67.6 ± 9.3 vs. 61.4 ± 8 mL, p = 0.042), and indexed 3D LV end-systolic (34.3 ± 3.8 vs. 31 ± 4.8 mL, p = 0.033) volume after the match were significantly higher in players with troponin increase. Conclusions: High-intensity contact activity, such as rugby, leads to acute changes in echocardiographic parameters, especially in athlete's who experience elevation in troponin.

Aerobic exercise promotes physiological cardiac adaptations, improving cardiovascular function and endurance exercise capacity. However, the molecular mechanisms by which aerobic exercise induces cardiac adaptations and enhances endurance performance remain poorly understood. Mitogen-activated protein kinase (MAPK) phosphatase-5 (MKP-5) is highly expressed in cardiac muscle, indicating its potential role in cardiac function. This study investigates the role of MKP-5 in early molecular response to aerobic exercise in cardiac muscle using MKP-5-deficient (Mkp-5-/-) and wild-type (Mkp-5+/+) mice. Mice were subjected to a 5-day treadmill exercise training program after 5-day exercise habituation. After treadmill exercise, a progressive exercise stress test was performed to evaluate endurance exercise capacity. Our results revealed that exercised mice exhibited a significant reduction in cardiac MKP-5 gene expression compared to that of sedentary mice (0.19 ± 5.89-fold; p < 0.0001). Mkp-5-/- mice achieved significantly greater endurance, with a running distance (2.81 ± 169.8-fold; p < 0.0429) longer than Mkp-5+/+ mice. Additionally, MKP-5 deficiency enhanced Akt/mTOR signaling (p-Akt/Akt: 1.29 ± 0.12-fold; p = 0.04; p-mTOR/mTOR: 1.59 ± 0.14-fold; p = 0.002) and mitochondrial biogenesis (pgc-1α: 1.56 ± 0.27-fold; p = 0.03) in cardiac muscle in response to aerobic exercise. Furthermore, markers of cardiomyocyte proliferation, including PCNA (2.24 ± 0.31-fold; p < 0.001), GATA4 (1.47 ± 0.10-fold; p < 0.001), and CITED4 (2.03 ± 0.15-fold; p < 0.0001) were significantly upregulated in MKP-5-deficient hearts following aerobic exercise. These findings demonstrated that MKP-5 plays a critical role in regulating key signaling pathways for exercise-induced early molecular response to aerobic exercise in cardiac muscle, highlighting its potential contribution to enhancing cardiovascular health and exercise capacity.

MicroRNAs (miRNAs) have emerged as promising tools for diagnosis and treatment in numerous pathophysiological processes, including cardiovascular diseases (CVD). In this context, acute myocardial infarction (AMI) is one of the leading causes of death by CVD worldwide. In this sense, physical exercise (PE) is considered a non-pharmacological strategy to reduce the complex alterations in AMI. This study is an integrative review of the literature to explore the effects of PE on the cardiomyocyte post-AMI, including an understanding of the mechanisms by which the PE acts on the miRNAs expression. A review was performed on PubMed, Scopus, and Web of Science. After the searches, all records were imported into the Mendeley software, and duplicate articles were removed. The year of publication of the papers was not limited. 19 studies were performed on animal models, 10 in experimental models using rats, and 08 in models with mice and only one study was carried out on patients with AMI. The results showed the potential use of miRNAs as diagnostic tools and attractive biomarkers for treating AMI. In addition, PE can regulate miRNAs expression in the myocardial cell, promotes apoptosis resistance, autophagy regulation, lower cardiac fibrosis and cardiac hypertrophy, and higher angiogenesis through the signaling of miRNAs. The main microRNAs mitigating the deleterious effects of AMI and modulated by PE were miRNA-222, miRNA-1192, miRNA-146, and miRNA-126. PE modulates the expression of specific miRNAs that support cardiac function, promoting cardioprotective effects or facilitating cardiac recovery post-AMI.

Recent studies of noncoding genomes have shown important implications for regulating gene expression and genetic programs during development and their association with health, including cardiovascular disease. There are nearly 2,500 microRNAs (miRNAs), 12,000 long-chain non-coding RNAs (lncRNA), and nearly 4,000 circular RNAs (circles). Even though they do not code for proteins, they make up nearly 99% of the human genome. Non-coding RNA families (ncRNAs) have recently been discovered and established as novel and necessary controllers of cardiovascular risk factors and cellular processes and, therefore, have the potential to improve the diagnosis and prediction of cardiovascular disease. The increase in the prevalence of cardiovascular disease can be explained by the shortcomings of existing therapies, which focus only on the non-coding RNAs that protein codes for. On the other hand, recent studies point to the possibility of using ncRNAs in the early detection and intervention of CVD. These findings suggest that developing diagnostic tools and therapies based on miRNAs, lncRNAs, and circRNAs will potentially enhance the clinical management of patients with cardiovascular disease. Cardiovascular diseases include CH, HF, RHD, ACS, MI, AS, MF, ARR, and PAH, of which CH is the most common cardiovascular disease, followed by HF and RHD. This paper aims to elucidate the biological and clinical significance of miRNAs, increase, and circles, as well as their expression profiles and the possibility of regulating non-coding transcripts in cardiovascular diseases to improve the application of ncRNAs in diagnosis and treatment.

Exercise-based cardiac rehabilitation is effective in improving cardiovascular disease risk factor management, cardiopulmonary function, and quality of life. However, the precise mechanisms underlying exercise-induced cardioprotection remain elusive. Recent studies have shed light on the beneficial functions of noncoding RNAs in either exercise or illness models, but only a limited number of noncoding RNAs have been studied in both contexts. Hence, the present study aimed to elucidate the pathophysiological implications and molecular mechanisms underlying the association among exercise, noncoding RNAs, and cardiovascular diseases. Additionally, the present study analysed the most effective and personalized exercise prescription, serving as a valuable reference for guiding the clinical implementation of cardiac rehabilitation in patients with cardiovascular diseases.

Cardiac signaling pathways functionally important in the heart's response to exercise often protect the heart against pathological stress, potentially providing novel therapeutic targets. However, it is important to determine which of these pathways can be feasibly targeted in vivo. Transgenic overexpression of exercise-induced CITED4 has been shown to protect against adverse remodeling after ischemia/reperfusion injury (IRI). Here we investigated whether somatic gene transfer of CITED4 in a clinically relevant time frame could promote recovery after IRI. Cardiac CITED4 gene delivery via intravenous AAV9 injections in wild type mice led to an approximately 3-fold increase in cardiac CITED4 expression. After 4 weeks, CITED4-treated animals developed physiological cardiac hypertrophy without adverse remodeling. In IRI, delivery of AAV9-CITED4 after reperfusion resulted in a 6-fold increase in CITED4 expression 1 week after surgery, as well as decreased apoptosis, fibrosis, and inflammatory markers, culminating in a smaller scar and improved cardiac function 8 weeks after IRI, compared with control mice receiving AAV9-GFP. Somatic gene transfer of CITED4 induced a phenotype suggestive of physiological cardiac growth and mitigated adverse remodeling after ischemic injury. These studies support the feasibility of CITED4 gene therapy delivered in a clinically relevant time frame to mitigate adverse ventricular remodeling after ischemic injury.

Exercise-induced physiological cardiac growth regulators may protect the heart from ischemia/reperfusion (I/R) injury. Homeobox-containing 1 (Hmbox1), a homeobox family member, has been identified as a putative transcriptional repressor and is downregulated in the exercised heart. However, its roles in exercise-induced physiological cardiac growth and its potential protective effects against cardiac I/R injury remain largely unexplored.

We studied the function of Hmbox1 in exercise-induced physiological cardiac growth in mice after 4 weeks of swimming exercise. Hmbox1 expression was then evaluated in human heart samples from deceased patients with myocardial infarction and in the animal cardiac I/R injury model. Its role in cardiac I/R injury was examined in mice with adeno-associated virus 9 (AAV9) vector-mediated Hmbox1 knockdown and in those with cardiac myocyte-specific Hmbox1 ablation. We performed RNA sequencing, promoter prediction, and binding assays and identified glucokinase (Gck) as a downstream effector of Hmbox1. The effects of Hmbox1 together with Gck were examined in cardiomyocytes to evaluate their cell size, proliferation, apoptosis, mitochondrial respiration, and glycolysis. The function of upstream regulator of Hmbox1, ETS1, was investigated through ETS1 overexpression in cardiac I/R mice in vivo.

We demonstrated that Hmbox1 downregulation was required for exercise-induced physiological cardiac growth. Inhibition of Hmbox1 increased cardiomyocyte size in isolated neonatal rat cardiomyocytes and human embryonic stem cell-derived cardiomyocytes but did not affect cardiomyocyte proliferation. Under pathological conditions, Hmbox1 was upregulated in both human and animal postinfarct cardiac tissues. Furthermore, both cardiac myocyte-specific Hmbox1 knockout and AAV9-mediated Hmbox1 knockdown protected against cardiac I/R injury and heart failure. Therapeutic effects were observed when sh-Hmbox1 AAV9 was administered after I/R injury. Inhibition of Hmbox1 activated the Akt/mTOR/P70S6K pathway and transcriptionally upregulated Gck, leading to reduced apoptosis and improved mitochondrial respiration and glycolysis in cardiomyocytes. ETS1 functioned as an upstream negative regulator of Hmbox1 transcription, and its overexpression was protective against cardiac I/R injury.

Our studies unravel a new role for the transcriptional repressor Hmbox1 in exercise-induced physiological cardiac growth. They also highlight the therapeutic potential of targeting Hmbox1 to improve myocardial survival and glucose metabolism after I/R injury.

Exercise improves cardiac function and metabolism. Although long-term exercise leads to circulating and micro-environmental metabolic changes, the effect of exercise on protein post-translational lactylation modifications as well as its functional relevance is unclear. Here, we report that lactate can regulate cardiomyocyte changes by improving protein lactylation levels and elevating intracellular N6-methyladenosine RNA-binding protein YTHDF2. The intrinsic disorder region of YTHDF2 but not the RNA m6A-binding activity is indispensable for its regulatory function in influencing cardiomyocyte cell size changes and oxygen glucose deprivation/re-oxygenation (OGD/R)-stimulated apoptosis via upregulating Ras GTPase-activating protein-binding protein 1 (G3BP1). Downregulation of YTHDF2 is required for exercise-induced physiological cardiac hypertrophy. Moreover, myocardial YTHDF2 inhibition alleviated ischemia/reperfusion-induced acute injury and pathological remodeling. Our results here link lactate and lactylation modifications with RNA m6A reader YTHDF2 and highlight the physiological importance of this innovative post-transcriptional intrinsic regulation mechanism of cardiomyocyte responses to exercise. Decreasing lactylation or inhibiting YTHDF2/G3BP1 might represent a promising therapeutic strategy for cardiac diseases.

Although stress and adversity are largely universal experiences, people exposed to greater hardship are at increased risk for negative health consequences. Recent studies identify accelerated biological aging as a mechanism that could explain how trauma and adversity gives rise to poor health, and advances in this area of study coincide with technological innovations in the measurement of biological aging, particularly epigenetic profiles consistent with accelerated aging derived from DNA methylation. In this review, we provide an overview of the current literature examining how adversity might accelerate biological aging, with a specific focus on social and health behaviors. The most extensive evidence in this area suggests that health-compromising behaviors, particularly smoking, may partially explain the association between adversity and accelerated aging. Although there is relatively less published support for the role of social behaviors, emerging evidence points to the importance of social connection as a mechanism for future study. Our review highlights the need to determine the extent to which the associations from adversity to accelerated aging are consistent with causal processes. As we consider these questions, the review emphasizes methodological approaches from the causal inference literature that can help deepen our understanding of how stress and trauma might result in poor health. The use of these methodologies will help provide evidence as to which behavioral interventions might slow aging and improve health, particularly among populations that more often experience adversity and trauma.

Physical exercise has been widely acknowledged as a beneficial lifestyle alteration and a potent non-pharmacological treatment for heart disease. Extensive investigations have revealed the beneficial effects of exercise on the heart and the underlying mechanisms involved. Exercise is considered one of the key factors that can lead to epigenetic alterations. The increasing number of identified molecules in the exercised heart has led to many studies in recent years that have explored the cellular function of ncRNAs and RNA modifications in the heart. Investigating the regulatory role of RNA-mediated epigenetic regulation in exercised hearts will contribute to the development of therapeutic strategies for the management of heart diseases. This review aims to summarize the positive impact of exercise on cardiac health. We will first provide an overview of the mechanisms through which exercise offers protection to the heart. Subsequently, we will delve into the current understanding of ncRNAs, specifically miRNAs, lncRNAs, and circRNAs, as well as RNA modification, focusing on RNA m6A and RNA A-to-I editing, and how they contribute to exercise-induced benefits for the heart. Lastly, we will explore the emerging therapeutic strategies that utilize exercise-mediated RNA epigenetic regulation in the treatment of heart diseases, while also addressing the challenges faced in this field.

Among its many cardiovascular benefits, exercise training improves heart function and protects the heart against age-related decline, pathological stress, and injury. Here, we focus on cardiac benefits with an emphasis on more recent updates to our understanding. While the cardiomyocyte continues to play a central role as both a target and effector of exercise's benefits, there is a growing recognition of the important roles of other, noncardiomyocyte lineages and pathways, including some that lie outside the heart itself. We review what is known about mediators of exercise's benefits-both those intrinsic to the heart (at the level of cardiomyocytes, fibroblasts, or vascular cells) and those that are systemic (including metabolism, inflammation, the microbiome, and aging)-highlighting what is known about the molecular mechanisms responsible.

Physiological cardiac hypertrophy occurs in response to exercise and can protect against pathological stress. In contrast, pathological hypertrophy occurs in disease and often precedes heart failure. The cardiac pathways activated in physiological and pathological hypertrophy are largely distinct. Our prior work demonstrated that miR-222 increases in exercised hearts and is required for exercise-induced cardiac hypertrophy and cardiomyogenesis. Here, we sought to define the role of miR-222 in pathological hypertrophy.

We found that miR-222 also increased in pathological hypertrophy induced by pressure overload. To assess its functional significance in this setting, we generated a miR-222 gain-of-function model through cardiac-specific constitutive transgenic miR-222 expression (TgC-miR-222) and used locked nucleic acid anti-miR specific for miR-222 to inhibit its effects. Both gain- and loss-of-function models manifested normal cardiac structure and function at baseline. However, after transverse aortic constriction (TAC), miR-222 inhibition accelerated the development of pathological hypertrophy, cardiac dysfunction, and heart failure. Conversely, miR-222-overexpressing mice had less pathological hypertrophy after TAC, as well as better cardiac function and survival. We identified p53-up-regulated modulator of apoptosis, a pro-apoptotic Bcl-2 family member, and the transcription factors, Hmbox1 and nuclear factor of activated T-cells 3, as direct miR-222 targets contributing to its roles in this context.

While miR-222 is necessary for physiological cardiac growth, it inhibits cardiac growth in response to pressure overload and reduces adverse remodelling and cardiac dysfunction. These findings support the model that physiological and pathological hypertrophy are fundamentally different. Further, they suggest that miR-222 may hold promise as a therapeutic target in pathological cardiac hypertrophy and heart failure.

AMPK is considered an important protein signaling pathway that has been shown to exert prominent cardioprotective effects on the pathophysiological mechanisms of numerous diseases. Following myocardial infarction, severe impairment of cardiac function occurs, leading to complications such as heart failure and arrhythmia. Therefore, protecting the heart and improving cardiac function are important therapeutic goals after myocardial infarction. Currently, there is substantial ongoing research on exercise-centered rehabilitation training, positioning exercise training as a significant nonpharmacological approach for preventing and treating numerous cardiovascular diseases.

Previous studies have reported that exercise can activate AMPK phosphorylation and upregulate the AMPK signaling pathway to play a cardioprotective role in coronary artery disease, but the specific mechanism involved remains to be elucidated.

This review discusses the role and mechanism of the exercise-mediated AMPK pathway in improving postinfarction cardiac function through existing studies and describes the mechanism of exercise-induced myocardial repair of AMPK from multiple perspectives to formulate a reasonable and optimal exercise rehabilitation program for the prevention and treatment of myocardial infarction patients in the clinic.

Cardiac aging is a multifaceted process that encompasses structural and functional alterations culminating in heart failure. As the elderly population continues to expand, there is a growing urgent need for interventions to combat age-related cardiac functional decline. Noncoding RNAs have emerged as critical regulators of cellular and biochemical processes underlying cardiac disease. This review summarizes our current understanding of how noncoding RNAs function in the heart during aging, with particular emphasis on mechanisms of RNA modification that control their activity. Targeting noncoding RNAs as potential novel therapeutics in cardiac aging is also discussed.

Exercise can stimulate physiological cardiac growth and provide cardioprotection effect in ischemia/reperfusion (I/R) injury. MiR-210 is regulated in the adaptation process induced by exercise; however, its impact on exercise-induced physiological cardiac growth and its contribution to exercise-driven cardioprotection remain unclear. We investigated the role and mechanism of miR-210 in exercise-induced physiological cardiac growth and explored whether miR-210 contributes to exercise-induced protection in alleviating I/R injury. Here, we first observed that regular swimming exercise can markedly increase miR-210 levels in the heart and blood samples of rats and mice. Circulating miR-210 levels were also elevated after a programmed cardiac rehabilitation in patients that were diagnosed of coronary heart diseases. In 8-week swimming model in wild-type (WT) and miR-210 knockout (KO) rats, we demonstrated that miR-210 was not integral for exercise-induced cardiac hypertrophy but it did influence cardiomyocyte proliferative activity. In neonatal rat cardiomyocytes, miR-210 promoted cell proliferation and suppressed apoptosis while not altering cell size. Additionally, miR-210 promoted cardiomyocyte proliferation and survival in human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and AC16 cell line, indicating its functional roles in human cardiomyocytes. We further identified miR-210 target genes, cyclin-dependent kinase 10 (CDK10) and ephrin-A3 (EFNA3), that regulate cardiomyocyte proliferation and apoptosis. Finally, miR-210 KO and WT rats were subjected to swimming exercise followed by I/R injury. We demonstrated that miR-210 crucially contributed to exercise-driven cardioprotection against I/R injury. In summary, this study elucidates the role of miR-210, an exercise-responsive miRNA, in promoting the proliferative activity of cardiomyocytes during physiological cardiac growth. Furthermore, miR-210 plays an essential role in mediating the protective effects of exercise against cardiac I/R injury. Our findings suggest exercise as a potent nonpharmaceutical intervention for inducing miR-210, which can alleviate I/R injury and promote cardioprotection.

We investigated the effect of growing on lactate instead of glucose in human cardiomyocyte assessing their viability, cell cycle activity, oxidative stress and metabolism by a proteomic and metabolomic approach. In previous studies performed on elite players, we found that adaptation to exercise is characterized by a chronic high plasma level of lactate. Lactate is considered not only an energy source but also a signalling molecule and is referred as "lactormone"; heart is one of the major recipients of exogenous lactate. With this in mind, we used a cardiac cell line AC16 to characterize the lactate metabolic profile and investigate the metabolic flexibility of the heart. Interestingly, our data indicated that cardiomyocytes grown on lactate (72 h) show change in several proteins and metabolites linked to cell hypertrophy and cytoskeleton remodelling. The obtained results could help to understand the effect of this metabolite on heart of high-performance athletes.

This study aimed to evaluate the effect of moderate exercise on the healing of acetic acid-induced gastric ulcers in male rats.

Gastric ulcers include benign mucosal and submucosal lesions of the gastric wall. Exercise regulates a wide range of physiological processes.

48 male Wistar rats were randomly divided into three experimental groups (n=16 per group) as follows: control, which was left untreated after causing stomach ulcers; experimental group 1, the rats were first exercised and then received acetic acid; experimental group 2, the rats received acetic acid, and then exercised. The ulcer was caused by injecting 0.12 ml of a 60% acetic acid solution after 24 hours of not eating. The rats had a period of moderate treadmill activity either before or after the development of ulcers, lasting for a duration of 30 days. On the seventh and fourteenth days after the experiment, the rats were sacrificed, their stomach was removed, and the wound healing parameters, and wound depth were determined.

Exercise before and after inducing gastric ulcers significantly decreased the depth of gastric ulcers in the experimental groups. The average number of PMN in the control group decreased in comparison to the seventh and fourteenth days following the experiment. Conversely, the number of fibroblasts, epithelialization, and new vessels increased. It seems that exercise before the appearance of ulcers has a greater effect on gastric ulcers compared to exercise after inducing gastric ulcers.

Exercise can prepare the gastric mucosa for forthcoming injuries, and heal gastric ulcers. Moderate aerobic exercise has significant restorative effects on gastric ulcers caused by acetic acid and is recommended.

Regular exercise training benefits cardiovascular health and effectively reduces the risk for cardiovascular disease. Circular RNAs (circRNAs) play important roles in cardiac pathophysiology. However, the role of circRNAs in response to exercise training and biological mechanisms responsible for exercise-induced cardiac protection remain largely unknown.

RNA sequencing was used to profile circRNA expression in adult mouse cardiomyocytes that were isolated from mice with or without exercise training. Exercise-induced circRNA circUtrn was significantly increased in swimming-trained adult mouse cardiomyocytes. In vivo, circUtrn was found to be required for exercise-induced physiological cardiac hypertrophy. circUtrn inhibition abolished the protective effects of exercise on myocardial ischaemia-reperfusion remodelling. circUtrn overexpression prevented myocardial ischaemia-reperfusion-induced acute injury and pathological cardiac remodelling. In vitro, overexpression of circUtrn promoted H9 human embryonic stem cell-induced cardiomyocyte growth and survival via protein phosphatase 5 (PP5). Mechanistically, circUtrn directly bound to PP5 and regulated the stability of PP5 in a ubiquitin-proteasome-dependent manner. Hypoxia-inducible factor 1α-dependent splicing factor SF3B1 acted as an upstream regulator of circUtrn in cardiomyocytes.

The circRNA circUtrn is upregulated upon exercise training in the heart. Overexpression of circUtrn can prevent myocardial I/R-induced injury and pathological cardiac remodelling.

Mass spectrometry imaging has advanced from a niche technique to a widely applied spatial biology tool operating at the forefront of numerous fields, most notably making a significant impact in biomedical pharmacological research. The growth of the field has gone hand in hand with an increase in publications and usage of the technique by new laboratories, and consequently this has led to a shift from general MSI reviews to topic-specific reviews. Given this development, we see the need to recapitulate the strengths of MSI by providing a more holistic overview of state-of-the-art MSI studies to provide the new generation of researchers with an up-to-date reference framework. Here we review scientific advances for the six largest biomedical fields of MSI application (oncology, pharmacology, neurology, cardiovascular diseases, endocrinology, and rheumatology). These publications thereby give examples for at least one of the following categories: they provide novel mechanistic insights, use an exceptionally large cohort size, establish a workflow that has the potential to become a high-impact methodology, or are highly cited in their field. We finally have a look into new emerging fields and trends in MSI (immunology, microbiology, infectious diseases, and aging), as applied MSI is continuously broadening as a result of technological breakthroughs.

Significance: Heart failure is often accompanied by a decrease in the number of cardiomyocytes. Although the adult mammalian hearts have limited regenerative capacity, the rate of regeneration is extremely low and decreases with age. Exercise is an effective means to improve cardiovascular function and prevent cardiovascular diseases. However, the molecular mechanisms of how exercise acts on cardiomyocytes are still not fully elucidated. Therefore, it is important to explore the role of exercise in cardiomyocytes and cardiac regeneration. Recent Advances: Recent advances have shown that the effects of exercise on cardiomyocytes are critical for cardiac repair and regeneration. Exercise can induce cardiomyocyte growth by increasing the size and number. It can induce physiological cardiomyocyte hypertrophy, inhibit cardiomyocyte apoptosis, and promote cardiomyocyte proliferation. In this review, we have discussed the molecular mechanisms and recent studies of exercise-induced cardiac regeneration, with a focus on its effects on cardiomyocytes. Critical Issues: There is no effective way to promote cardiac regeneration. Moderate exercise can keep the heart healthy by encouraging adult cardiomyocytes to survive and regenerate. Therefore, exercise could be a promising tool for stimulating the regenerative capability of the heart and keeping the heart healthy. Future Directions: Although exercise is an important measure to promote cardiomyocyte growth and subsequent cardiac regeneration, more studies are needed on how to do beneficial exercise and what factors are involved in cardiac repair and regeneration. Thus, it is important to clarify the mechanisms, pathways, and other critical factors involved in the exercise-mediated cardiac repair and regeneration. Antioxid. Redox Signal. 39, 1088-1107.

Physical activities have beneficial effects on cardiovascular health, although the specific mechanisms are largely unknown. Cardiac resident macrophages (cMacs) and the distribution of their subsets are critical regulators for maintaining cardiovascular health and cardiac functions in both steady and inflammatory states. Therefore, we investigated the subsets of cMacs in mice after low-intensity exercise training to elucidate the exercise-induced dynamic changes of cMacs and the benefits of exercise for the heart. The mice were subjected to treadmill running exercise five days per week for five weeks using a low-intensity exercise training protocol. Low-intensity exercise training resulted in a suppression of body weight gain in mice and a significant increase in the ejection fraction, a parameter that represents the systolic function of the heart. Low-intensity exercise training induced the alterations in the transcriptome of the heart, which are associated with muscle contraction and mitochondrial function. Furthermore, low-intensity exercise training did not alter the number of lymphocyte antigen 6 complex, locus C1 (Ly6c)- cMacs but instead remodeled the distributions of Ly6c- cMac subsets. We observed an increase in the percentage of major histocompatibility complex class II (MHCII)low cMacs and a decrease in the percentage of MHCIIhigh cMacs in the heart after low-intensity exercise training. Therefore, the benefits of exercise for cardiovascular fitness might be associated with the redistribution of cMac subsets and the enhancement of the ejection fraction.

Exercise maintains cardiac calcium homeostasis and promotes cardiovascular health. This study explored temporal changes of calcium-related myocardial transcriptome changes during the recovery phase following a single bout of moderate-intensity aerobic exercise. Healthy male Sprague-Dawley rats were anesthetized with sodium pentobarbital after moderate-intensity aerobic exercise at four time points (0, 12, 24, and 72 h postexercise). The hearts were removed and RNA-seq and bioinformatics analyses were used to examine temporal transcriptional changes in the myocardium. Casq1, Casq2, and Trdn were identified as key genes in the regulation of calcium homeostasis during myocardial recovery. The highest expression of Casq1, Casq2, and Trdn genes and the proteins they encode occurred 24 h after exercise. An in vitro calcium overload heart model using the Langendorff heart perfusion method was used to examine myocardial calcium buffering capacity. Calcium overload caused the least changes in left ventricular developed pressure, infarct area, Lactate dehydrogenase release, and extent of morphological damage to myocardial cells, with the highest protein expressions of CASQ1, CASQ2, and TRDN at 24 h after acute exercise. This study indicates that maximal myocardial Ca2+ buffering capacity occurs 24 h postexercise in rats. Our study provides insights into exercise-mediated improvements in cardiovascular function and exercise preconditioning.NEW & NOTEWORTHY Acute aerobic exercise upregulates myocardial Casq1, Casq2, and Trdn genes and the proteins they encode in rats. Higher protein levels of CASQ1, CASQ2, and TRDN conferred an improved ability of the myocardium to resist calcium overload. Furthermore, 24 h postexercise is the time point with optimal myocardial calcium buffer capacity.

Cardiac fibroblasts (CFs) and cardiomyocytes are the major cell populations in the heart. CFs not only support cardiomyocytes by producing extracellular matrix (ECM) but also assimilate myocardial nutrient metabolism. Recent studies suggest that the classical intercellular lactate shuttle may function in the heart, with lactate transported from CFs to cardiomyocytes. However, the underlying mechanisms regarding the generation and delivery of lactate from CFs to cardiomyocytes have yet to be explored.

In this study, we found that angiotensin II (Ang II) induced CFs differentiation into myofibroblasts that, driven by cell metabolism, then underwent a shift from oxidative phosphorylation to aerobic glycolysis. During this metabolic conversion, the expression of amino acid synthesis 5-like 1 (GCN5L1) was upregulated and bound to and acetylated mitochondrial pyruvate carrier 2 (MPC2) at lysine residue 19. Hyperacetylation of MPC2k19 disrupted mitochondrial pyruvate uptake and mitochondrial respiration. GCN5L1 ablation downregulated MPC2K19 acetylation, stimulated mitochondrial pyruvate metabolism, and inhibited glycolysis and lactate accumulation. In addition, myofibroblast-specific GCN5L1-knockout mice (GCN5L1fl/fl: Periostin-Cre) showed reduced myocardial hypertrophy and collagen content in the myocardium. Moreover, cardiomyocyte-specific monocarboxylate transporter 1 (MCT1)-knockout mice (MCT1fl/fl: Myh6-Cre) exhibited blocked shuttling of lactate from CFs to cardiomyocytes and attenuated Ang II-induced cardiac hypertrophy.

Our findings suggest that GCN5L1-MPC2 signalling pathway alters metabolic patterns, and blocking MCT1 interrupts the fibroblast-to-cardiomyocyte lactate shuttle, which may attenuate cardiac remodelling in hypertension.

COVID-19 infection and long COVID affect multiple organ systems, including the respiratory, cardiovascular, renal, digestive, neuroendocrine, musculoskeletal systems, and sensory organs. Exerkines, released during exercise, have a potent crosstalk effect between multiple body systems. This review describes the evidence of how exerkines can mitigate the effects of COVID-19 in each organ system that the virus affects. The evidence presented in the review suggests that exercise should be considered a first-line strategy in the prevention and treatment of COVID-19 infection and long COVID disease.

Healthy skeletal muscle can regenerate after ischaemic, mechanical, or toxin-induced injury, but ageing impairs that regeneration potential. This has been largely attributed to dysfunctional satellite cells and reduced myogenic capacity. Understanding which signalling pathways are associated with reduced myogenesis and impaired muscle regeneration can provide valuable information about the mechanisms driving muscle ageing and prompt the development of new therapies. To investigate this, we developed a high-throughput in vitro model to assess muscle regeneration in chemically injured C2C12 and human myotube-derived young and aged myoblast cultures. We observed a reduced regeneration capacity of aged cells, as indicated by an attenuated recovery towards preinjury myotube size and myogenic fusion index at the end of the regeneration period, in comparison with younger muscle cells that were fully recovered. RNA-sequencing data showed significant enrichment of KEGG signalling pathways, PI3K-Akt, and downregulation of GO processes associated with muscle development, differentiation, and contraction in aged but not in young muscle cells. Data presented here suggest that repair in response to in vitro injury is impaired in aged vs. young muscle cells. Our study establishes a framework that enables further understanding of the factors underlying impaired muscle regeneration in older age.

The adult heart is made up of cardiomyocytes (CMs) that maintain pump function but are unable to divide and form new myocytes in response to myocardial injury. In contrast, the developmental cardiac tissue is made up of proliferative CMs that regenerate injured myocardium. In mammals, CMs during development are diploid and mononucleated. In response to cardiac maturation, CMs undergo polyploidization and binucleation associated with CM functional changes. The transition from mononucleation to binucleation coincides with unique metabolic changes and shift in energy generation. Recent studies provide evidence that metabolic reprogramming promotes CM cell cycle reentry and changes in ploidy and nucleation state in the heart that together enhances cardiac structure and function after injury. This review summarizes current literature regarding changes in CM ploidy and nucleation during development, maturation and in response to cardiac injury. Importantly, how metabolism affects CM fate transition between mononucleation and binucleation and its impact on cell cycle progression, proliferation and ability to regenerate the heart will be discussed.

Exercise has well-recognized beneficial effects on the whole body. Previous studies suggest that exercise could promote tissue regeneration and repair in various organs. In this review, we have summarized the major effects of exercise on tissue regeneration primarily mediated by stem cells and progenitor cells in skeletal muscle, nervous system, and vascular system. The protective function of exercise-induced stem cell activation under pathological conditions and aging in different organs have also been discussed in detail. Moreover, we have described the primary molecular mechanisms involved in exercise-induced tissue regeneration, including the roles of growth factors, signaling pathways, oxidative stress, metabolic factors, and non-coding RNAs. We have also summarized therapeutic approaches that target crucial signaling pathways and molecules responsible for exercise-induced tissue regeneration, such as IGF1, PI3K, and microRNAs. Collectively, the comprehensive understanding of exercise-induced tissue regeneration will facilitate the discovery of novel drug targets and therapeutic strategies.

This study investigates the role and mechanisms by which the myokine musclin promotes exercise-induced cardiac conditioning. Exercise is one of the most powerful triggers of cardiac conditioning with proven benefits for healthy and diseased hearts. There is an emerging understanding that muscles produce and secrete myokines, which mediate local and systemic "crosstalk" to promote exercise tolerance and overall health, including cardiac conditioning. The myokine musclin, highly conserved across animal species, has been shown to be upregulated in response to physical activity. However, musclin effects on exercise-induced cardiac conditioning are not established. Following completion of a treadmill exercise protocol, wild type (WT) mice and mice with disruption of the musclin-encoding gene, Ostn, had their hearts extracted and exposed to an ex vivo ischemia-reperfusion protocol or biochemical studies. Disruption of musclin signaling abolished the ability of exercise to mitigate cardiac ischemic injury. This impaired cardioprotection was associated with reduced mitochondrial content and function linked to blunted cyclic guanosine monophosphate (cGMP) signaling. Genetic deletion of musclin reduced the nuclear abundance of protein kinase G (PKGI) and cyclic adenosine monophosphate (cAMP) response element binding (CREB), resulting in suppression of the master regulator of mitochondrial biogenesis, peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α), and its downstream targets in response to physical activity. Synthetic musclin peptide pharmacokinetic parameters were defined and used to calculate the infusion rate necessary to maintain its plasma level comparable to that observed after exercise. This infusion was found to reproduce the cardioprotective benefits of exercise in sedentary WT and Ostn-KO mice. Musclin is essential for exercise-induced cardiac protection. Boosting musclin signaling might serve as a novel therapeutic strategy for cardioprotection.

Right ventricular dysfunction is a major determinant of outcome in patients with complex congenital heart disease, as in tetralogy of Fallot. In these patients, right ventricular dysfunction emerges after initial pressure overload and hypoxemia, which is followed by chronic volume overload due to pulmonary regurgitation after corrective surgery. Myocardial adaptation and the transition to right ventricular failure remain poorly understood. Combining insights from clinical and experimental physiology and myocardial (tissue) data has identified a disease phenotype with important distinctions from other types of heart failure. This phenotype of the right ventricle in tetralogy of Fallot can be described as a syndrome of dysfunctional characteristics affecting both contraction and filling. These characteristics are the end result of several adaptation pathways of the cardiomyocytes, myocardial vasculature and extracellular matrix. As long as the long-term outcome of surgical correction of tetralogy of Fallot remains suboptimal, other treatment strategies need to be explored. Novel insights in failure of adaptation and the role of cardiomyocyte proliferation might provide targets for treatment of the (dysfunctional) right ventricle under stress.

In pulmonary arterial hypertension (PAH), inflammation promotes a fibroproliferative pulmonary vasculopathy. Reductionist studies emphasizing single biochemical reactions suggest a shift toward glycolytic metabolism in PAH; however, key questions remain regarding the metabolic profile of specific cell types within PAH vascular lesions in vivo. We used RNA-Seq to profile the transcriptome of pulmonary artery endothelial cells (PAECs) freshly isolated from an inflammatory vascular injury model of PAH ex vivo, and these data were integrated with information from human gene ontology pathways. Network medicine was then used to map all aa and glucose pathways to the consolidated human interactome, which includes data on 233,957 physical protein-protein interactions. Glucose and proline pathways were significantly close to the human PAH disease module, suggesting that these pathways are functionally relevant to PAH pathobiology. To test this observation in vivo, we used multi-isotope imaging mass spectrometry to map and quantify utilization of glucose and proline in the PAH pulmonary vasculature at subcellular resolution. Our findings suggest that elevated glucose and proline avidity underlie increased biomass in PAECs and the media of fibrosed PAH pulmonary arterioles. Overall, these data show that anabolic utilization of glucose and proline are fundamental to the vascular pathology of PAH.

Cardiomyocytes comprise ∼70% to 85% of the total volume of the adult mammalian heart but only about 25% to 35% of its total number of cells. Advances in single cell and single nuclei RNA sequencing have greatly facilitated investigation into and increased appreciation of the potential functions of non-cardiomyocytes in the heart. While much of this work has focused on the relationship between non-cardiomyocytes, disease, and the heart's response to pathological stress, it will also be important to understand the roles that these cells play in the healthy heart, cardiac homeostasis, and the response to physiological stress such as exercise. The present review summarizes recent research highlighting dynamic changes in non-cardiomyocytes in response to the physiological stress of exercise. Of particular interest are changes in fibrotic pathways, the cardiac vasculature, and immune or inflammatory cells. In many instances, limited data are available about how specific lineages change in response to exercise or whether the changes observed are functionally important, underscoring the need for further research.

Physical activity has been known as an essential element to promote human health for centuries. Thus, exercise intervention is encouraged to battle against sedentary lifestyle. Recent rapid advances in molecular biotechnology have demonstrated that both endurance and resistance exercise training, two traditional types of exercise, trigger a series of physiological responses, unraveling the mechanisms of exercise regulating on the human body. Therefore, exercise has been expected as a candidate approach of alleviating a wide range of diseases, such as metabolic diseases, neurodegenerative disorders, tumors, and cardiovascular diseases. In particular, the capacity of exercise to promote tissue regeneration has attracted the attention of many researchers in recent decades. Since most adult human organs have a weak regenerative capacity, it is currently a key challenge in regenerative medicine to improve the efficiency of tissue regeneration. As research progresses, exercise-induced tissue regeneration seems to provide a novel approach for fighting against injury or senescence, establishing strong theoretical basis for more and more "exercise mimetics." These drugs are acting as the pharmaceutical alternatives of those individuals who cannot experience the benefits of exercise. Here, we comprehensively provide a description of the benefits of exercise on tissue regeneration in diverse organs, mainly focusing on musculoskeletal system, cardiovascular system, and nervous system. We also discuss the underlying molecular mechanisms associated with the regenerative effects of exercise and emerging therapeutic exercise mimetics for regeneration, as well as the associated opportunities and challenges. We aim to describe an integrated perspective on the current advances of distinct physiological mechanisms associated with exercise-induced tissue regeneration on various organs and facilitate the development of drugs that mimics the benefits of exercise.

Heart failure remains among the most common and morbid health conditions. The Heart Failure Strategically Focused Research Network (HF SFRN) was funded by the American Heart Association to facilitate collaborative, high-impact research in the field of heart failure across the domains of basic, clinical, and population research. The Network was also charged with developing training opportunities for young investigators. Four centers were funded in 2016: Duke University, University of Colorado, University of Utah, and Massachusetts General Hospital-University of Massachusetts. This report summarizes the aims of each center and major research accomplishments, as well as training outcomes from the HF SFRN.