Physical exercise shapes the mouse brain epigenome.

OBJECTIVE: To analyze the genome-wide epigenomic and transcriptomic changes induced by long term resistance or endurance training in the hippocampus of wild-type mice. METHODS: We performed whole-genome bisulfite sequencing (WGBS) and RNA sequencing (RNA-seq) of mice hippocampus after 4 weeks of specific training. In addition, we used a novel object recognition test before and after the intervention to determine whether the exercise led to an improvement in cognitive function. RESULTS: Although the majority of DNA methylation changes identified in this study were training-model specific, most were associated with hypomethylation and were enriched in similar histone marks, chromatin states, and transcription factor biding sites. It is worth highlighting the significant association found between the loss of DNA methylation in Tet1 binding sites and gene expression changes, indicating the importance of these epigenomic changes in transcriptional regulation. However, endurance and resistance training activate different gene pathways, those being associated with neuroplasticity in the case of endurance exercise, and interferon response pathways in the case of resistance exercise, which also appears to be associated with improved learning and memory functions. CONCLUSIONS: Our results help both understand the molecular mechanisms by which different exercise models exert beneficial effects for brain health and provide new potential therapeutic targets for future research.

Circulating MicroRNA Profiling Reveals Specific Subsignatures in Response to a Maximal Incremental Exercise Test.

ABSTRACT: Fernández-Sanjurjo, M, Díaz-Martínez, ÁE, Díez-Robles, S, González-González, F, de Gonzalo-Calvo, D, Rabadán, M, Dávalos, A, Fernández-García, B, and Iglesias-Gutiérrez, E. Circulating microRNA profiling reveals specific subsignatures in response to a maximal incremental exercise test. J Strength Cond Res 35(2): 287-291, 2021-Circulating microRNAs (c-miRNAs) have been described as emergent regulators and biomarkers of exercise. The aim of this study was to analyze the c-miRNA response to a maximal incremental exercise test (MIET) and its relationship with markers of exercise response and adaptation. Two blood samples were collected from 9 male amateur runners (31-50 years), before (Pre) and after (Post) a MIET. The maximal oxygen uptake (V̇o2max), maximum heart rate (HRmax), and maximal aerobic speed (MAS) were recorded. Lactate and creatine kinase (CK) plasma concentrations were measured. A panel of 752 miRNAs was analyzed using standardized protocols and relative quantification to Pre. A total of 13 miRNAs were found significantly upregulated at Post. By focusing on the exercise markers that correlate with the expression of these miRNAs, they were clustered into different functional groups or subsignatures. Thus, miR-21-5p, miR-29b-3p, and miR-183-5p showed a strong correlation with HRmax and a validated target signature related to fatty acid metabolism. Furthermore, let-7c-5p, miR-340-5p, miR-425-3p, and miR-629-5p were significantly correlated with CK, and the most significantly enriched pathways for these subsignatures were the Hippo signaling pathway and signaling pathways regulating pluripotency of stem cells. Finally, Pre miR-106b-5p expression showed an inverse association with MAS and Post lactate concentration, which highlights its relevance as biomarker of training status and its predictive value for performance. No significant correlations were observed with V̇o2max. Our results define for the first time specific functional c-miRNA subsignatures, adding novel evidence about their potential regulatory role in exercise response.

Exercise dose affects the circulating microRNA profile in response to acute endurance exercise in male amateur runners.

The systemic response to exercise is dose-dependent and involves a complex gene expression regulation and cross-talk between tissues. This context ARISES the need for analyzing the influence of exercise dose on the profile of circulating microRNAs (c-miRNAs), as emerging posttranscriptional regulators and intercellular communicators. Thus, we hypothesized that different exercise doses will determine specific c-miRNA signatures that will highlight its potential as exercise dose biomarker. Nine active middle-aged males completed a 10-km race (10K), a half-marathon (HM), and a marathon (M). Blood samples were collected immediately before and after races. Plasma RNA was extracted, and a global screening of 752 microRNAs was analyzed using RT-qPCR. Three different c-miRNA profiles were defined according to the three doses. In 10K, 14 c-miRNAs were found to be differentially expressed between pre- and post-exercise, 13 upregulated and 1 downregulated. Regarding HM, 13 c-miRNAs were found to be differentially modulated, in all the cases upregulated. A total of 28 c-miRNAs were found to be differentially expressed in M, 21 overexpressed and 7 repressed after this race. We had also found 3 common c-miRNAs between 10K and M and 2 common c-miRNAs between 10K and HM. In silico analysis supported a close association between exercise dose c-miRNA profiles and cellular pathways linked to energy metabolism and cell cycle. In conclusion, we have observed that different exercise doses induced specific c-miRNA profiles. So, our results point to c-miRNAs as emerging exercise dose biomarkers and as one of regulatory mechanisms modulating the response to endurance exercise.

Autophagy is required for performance adaptive response to resistance training and exercise-induced adult neurogenesis.

Endurance training promotes exercise-induced adaptations in brain, like hippocampal adult neurogenesis and autophagy induction. However, resistance training effect on the autophagy response in the brain has not been much explored. Questions such as whether partial systemic autophagy or the length of training intervention affect this response deserve further attention. Therefore, 8-week-old male wild-type (Wt; n = 36) and systemic autophagy-deficient (atg4b-/- , KO; n = 36) mice were randomly distributed in three training groups, resistance (R), endurance (E), and control (non-trained), and in two training periods, 2 or 14 weeks. R and E maximal tests were evaluated before and after the training period. Forty-eight hours after the end of training program, cerebral cortex, striatum, hippocampus, and cerebellum were extracted for the analysis of autophagy proteins (LC3B-I, LC3B-II, and p62). Additionally, hippocampal adult neurogenesis was determined by doublecortin-positive cells count (DCX+) in brain sections. Our results show that, in contrast to Wt, KO were unable to improve R after both trainings. Autophagy levels in brain areas may be modified by E training only in cerebral cortex of Wt trained for 14 weeks, and in KO trained for 2 weeks. DCX + in Wt increased in R and E after both periods of training, with R for 14 weeks more effective than E. Interestingly, no changes in DCX + were observed in KO after 2 weeks, being even undetectable after 14 weeks of intervention. Thus, autophagy is crucial for R performance and for exercise-induced adult neurogenesis.

Circulating microRNA as Emerging Biomarkers of Exercise.

An interest has recently emerged in the role of circulating microRNAs (c-miRNAs) as posttranscriptional regulators, intercellular communicators and, especially, as potential biomarkers of the systemic response to acute exercise and training. We propose that, with the limited, heterogeneous, and mainly descriptive information currently available, c-miRNAs do not provide a reliable biomarker of exercise in healthy or diseased individuals.

MicroRNA circulantes como reguladores de la respuesta molecular al ejercicio en personas sanas / Circulating microRNA as regulators of the molecular response in exercise in healthy people

Los microRNAs circulantes (c-miRNAs) son reguladores de la expresión génica y mediadores de la comunicación intercelular, con un gran potencial como coordinadores de la respuesta molecular al ejercicio y, por tanto, con eventuales implicaciones prácticas para la salud y el rendimiento. Sin embargo, su respuesta al ejercicio agudo y al entrenamiento en personas sanas es poco conocida, principalmente porque hasta el momento se ha publicado un número reducido de artículos, con resultados dispares. El objetivo de esta revisión es agrupar y sintetizar el conocimiento disponible, analizar las causas de esta heterogeneidad en los resultados e identificar las principales perspectivas de futuro en esta área. Los resultados de los trabajos incluidos en esta revisión muestran que el ejercicio agudo y el entrenamiento inducen una respuesta en el perfil de c-miRNAs influida por el modelo, duración, intensidad y dosis de ejercicio. Queda pendiente, no obstante, conocer su origen, forma de transporte, destino, así como validar sus dianas génicas. Sin embargo, estos estudios muestran entre sí numerosas diferencias metodológicas (técnica de detección, número y tipo de c-miRNAs analizados, estrategia de normalización), en el diseño experimental (puntos de muestreo) y en las características de los sujetos (edad, historial de entrenamiento), que hace difícil, tanto establecer comparaciones directas entre ellos, como extraer conclusiones generales sólidas. Finalmente, este papel del ejercicio, como modulador del perfil de c-miRNAs, podría constituir una alternativa viable y coadyuvante a las terapias farmacológicas y dietéticas basadas en miRNAs que actualmente se encuentran en desarrollo. Además, su validación como biomarcadores de ejercicio podría contribuir al desarrollo de recomendaciones de ejercicio más precisas, a optimizar su aplicación como herramienta preventiva o terapéutica y a explorar los límites máximos del ejercicio saludable

Circulating microRNAs (c-miRNAs) are cell-to-cell communicators implicated in the regulation of molecular responses with strong potential in exercise and practical implications in health. Despite this fact, the number of papers published on this topic is scarce and with inconsistent results. Thus, the aim of this review was to summarize the information available, to analyze the heterogeneity of the results and to identify which are the future perspectives in this field of research. The results of the studies included in this revision clearly show that acute exercise and training induce a response in c-miRNA profile. This response depends on the model, intensity and dose of exercise. However, there are some questions which must be answered: what are the secretory organs or tissues, the mechanisms of transport, and the tissue and gene targets. A number of differences between studies in the methodologies used (detection technique, number of c-miRNAs analyzed, normalization strategy), in the experimental design (sampling points) and in the characteristics of the participants (aging, exercise background, dietary intake) makes it difficult to establish direct comparisons and to draw firm conclusions. Finally, this role of exercise as c-miRNA profile modulator, could be considered a valuable alternative to upcoming pharmacological and nutritional interventions based on miRNAs. Moreover, the validation of c-miRNAs as biomarkers of exercise will allow the development of more specific recommendations, using training as a therapeutic and preventive tool, and exploring the maximal limits for a safe and healthy exercise