1 2681 94 EVALUATION OF MUSCLE-SPECIFIC AND METABOLISM REGULATING MICRORNAS IN A CHRONIC SWIMMING RAT MODEL. MAKING BENEFIT FROM THE EPIGENETIC EFFECTS OF ENVIRONMENTAL FACTORS SUCH AS PHYSICAL ACTIVITY MAY RESULT IN A CONSIDERABLE IMPROVEMENT IN THE PREVENTION OF CHRONIC CIVILIZATION DISEASES. IN OUR CHRONIC SWIMMING RAT MODEL, THE EXPRESSION LEVELS OF SUCH MICRORNAS WERE CHARACTERIZED, THAT ARE INVOLVED IN SKELETAL MUSCLE DIFFERENTIATION, HYPERTROPHY AND FINE-TUNING OF METABOLISM, WHICH PROCESSES ARE INFLUENCED BY CHRONIC ENDURANCE TRAINING, CONTRIBUTING TO THE METABOLIC ADAPTATION OF SKELETAL MUSCLE DURING PHYSICAL ACTIVITY. AFTER CHRONIC SWIMMING, THE LEVEL OF MIR-128A INCREASED SIGNIFICANTLY IN EDL MUSCLES, WHICH MAY INFLUENCE METABOLIC ADAPTATION AND STRESS RESPONSE AS WELL. IN SOL, THE EXPRESSION LEVEL OF MIR-15B AND MIR-451 DECREASED SIGNIFICANTLY AFTER CHRONIC SWIMMING, WHICH CHANGES ARE OPPOSITE TO THEIR PREVIOUSLY DESCRIBED INCREMENT IN INSULIN RESISTANT SKELETAL MUSCLE. MIR-451 ALSO TARGETS PGC-1ALPHA MRNA, WHICHES EXPRESSION LEVEL SIGNIFICANTLY INCREASED IN SOL MUSCLES, RESULTING IN ENHANCED BIOGENESIS AND OXIDATIVE CAPACITY OF MITOCHONDRIA. IN SUMMARY, THE MICRORNA EXPRESSION CHANGES THAT WERE OBSERVED DURING OUR EXPERIMENTS SUGGEST THAT CHRONIC SWIM TRAINING CONTRIBUTES TO A BENEFICIAL METABOLIC PROFILE OF SKELETAL MUSCLE. 2022 2 2499 22 EPIGENETICS AND EXERCISE. EPIGENETICS CAN BE DEFINED AS 'THE STRUCTURAL ADAPTATION OF CHROMOSOMAL REGIONS SO AS TO REGISTER, SIGNAL, OR PERPETUATE ALTERED ACTIVITY STATES.' INCREASED TRANSCRIPTION OF KEY REGULATORY, METABOLIC, AND MYOGENIC GENES IS AN EARLY RESPONSE TO EXERCISE AND IS IMPORTANT IN MEDIATING SUBSEQUENT ADAPTATIONS IN SKELETAL MUSCLE. DNA HYPOMETHYLATION AND HISTONE HYPERACETYLATION ARE EMERGING AS IMPORTANT CRUCIAL EVENTS FOR INCREASED TRANSCRIPTION. THE COMPLEX INTERACTIONS BETWEEN MULTIPLE EPIGENETIC MODIFICATIONS AND THEIR REGULATION BY METABOLIC CHANGES AND SIGNALING EVENTS DURING EXERCISE, WITH IMPLICATIONS FOR ENHANCED UNDERSTANDING OF THE ACUTE AND CHRONIC ADAPTATIONS TO EXERCISE, ARE QUESTIONS FOR FURTHER INVESTIGATION. 2019 3 2408 28 EPIGENETIC REWIRING OF SKELETAL MUSCLE ENHANCERS AFTER EXERCISE TRAINING SUPPORTS A ROLE IN WHOLE-BODY FUNCTION AND HUMAN HEALTH. OBJECTIVES: REGULAR PHYSICAL EXERCISE IMPROVES HEALTH BY REDUCING THE RISK OF A PLETHORA OF CHRONIC DISORDERS. WE HYPOTHESIZED THAT ENDURANCE EXERCISE TRAINING REMODELS THE ACTIVITY OF GENE ENHANCERS IN SKELETAL MUSCLE AND THAT THIS REMODELING CONTRIBUTES TO THE BENEFICIAL EFFECTS OF EXERCISE ON HUMAN HEALTH. METHODS AND RESULTS: BY STUDYING CHANGES IN HISTONE MODIFICATIONS, WE MAPPED THE GENOME-WIDE POSITIONS AND ACTIVITIES OF ENHANCERS IN SKELETAL MUSCLE BIOPSIES COLLECTED FROM YOUNG SEDENTARY MEN BEFORE AND AFTER 6 WEEKS OF ENDURANCE EXERCISE. WE IDENTIFIED EXTENSIVE REMODELING OF ENHANCER ACTIVITIES AFTER EXERCISE TRAINING, WITH A LARGE SUBSET OF THE REMODELED ENHANCERS LOCATED IN THE PROXIMITY OF GENES TRANSCRIPTIONALLY REGULATED AFTER EXERCISE. BY OVERLAPPING THE POSITION OF ENHANCERS WITH GENETIC VARIANTS, WE IDENTIFIED AN ENRICHMENT OF DISEASE-ASSOCIATED GENETIC VARIANTS WITHIN THE EXERCISE-REMODELED ENHANCERS. CONCLUSION: OUR DATA PROVIDE EVIDENCE OF A FUNCTIONAL LINK BETWEEN EPIGENETIC REWIRING OF ENHANCERS TO CONTROL THEIR ACTIVITY AFTER EXERCISE TRAINING AND THE MODULATION OF DISEASE RISK IN HUMANS. 2021 4 3581 35 IMPACT OF PHYSICAL ACTIVITY AND EXERCISE ON THE EPIGENOME IN SKELETAL MUSCLE AND EFFECTS ON SYSTEMIC METABOLISM. EXERCISE AND PHYSICAL ACTIVITY INDUCES PHYSIOLOGICAL RESPONSES IN ORGANISMS, AND ADAPTATIONS IN SKELETAL MUSCLE, WHICH IS BENEFICIAL FOR MAINTAINING HEALTH AND PREVENTING AND/OR TREATING MOST CHRONIC DISEASES. THESE ADAPTATIONS ARE MAINLY INSTIGATED BY TRANSCRIPTIONAL RESPONSES THAT ENSUE IN REACTION TO EACH INDIVIDUAL EXERCISE, EITHER RESISTANCE OR ENDURANCE. CONSEQUENTLY, CHANGES IN KEY METABOLIC, REGULATORY, AND MYOGENIC GENES IN SKELETAL MUSCLE OCCUR AS BOTH AN EARLY AND LATE RESPONSE TO EXERCISE, AND THESE EPIGENETIC MODIFICATIONS, WHICH ARE INFLUENCED BY ENVIRONMENTAL AND GENETIC FACTORS, TRIGGER THOSE ALTERATIONS IN THE TRANSCRIPTIONAL RESPONSES. DNA METHYLATION AND HISTONE MODIFICATIONS ARE THE MOST SIGNIFICANT EPIGENETIC CHANGES DESCRIBED IN GENE TRANSCRIPTION, LINKED TO THE SKELETAL MUSCLE TRANSCRIPTIONAL RESPONSE TO EXERCISE, AND MEDIATING THE EXERCISE ADAPTATIONS. NEVERTHELESS, OTHER ALTERATIONS IN THE EPIGENETICS MARKERS, SUCH AS EPITRANSCRIPTOMICS, MODIFICATIONS MEDIATED BY MIRNAS, AND LACTYLATION AS A NOVEL EPIGENETIC MODIFICATION, ARE EMERGING AS KEY EVENTS FOR GENE TRANSCRIPTION. HERE, WE PROVIDE AN OVERVIEW AND UPDATE OF THE IMPACT OF EXERCISE ON EPIGENETIC MODIFICATIONS, INCLUDING THE WELL-DESCRIBED DNA METHYLATIONS AND HISTONE MODIFICATIONS, AND THE EMERGING MODIFICATIONS IN THE SKELETAL MUSCLE. IN ADDITION, WE DESCRIBE THE EFFECTS OF EXERCISE ON EPIGENETIC MARKERS IN OTHER METABOLIC TISSUES; ALSO, WE PROVIDE INFORMATION ABOUT HOW SYSTEMIC METABOLISM OR ITS METABOLITES INFLUENCE EPIGENETIC MODIFICATIONS IN THE SKELETAL MUSCLE. 2022 5 2713 29 EXERCISE TRAINING AND EPIGENETIC REGULATION: MULTILEVEL MODIFICATION AND REGULATION OF GENE EXPRESSION. EXERCISE TRAINING ELICITS ACUTE AND ADAPTIVE LONG TERM CHANGES IN HUMAN PHYSIOLOGY THAT MEDIATE THE IMPROVEMENT OF PERFORMANCE AND HEALTH STATE. THE RESPONSES ARE INTEGRATIVE AND ORCHESTRATED BY SEVERAL MECHANISMS, AS GENE EXPRESSION. GENE EXPRESSION IS ESSENTIAL TO CONSTRUCT THE ADAPTATION OF THE BIOLOGICAL SYSTEM TO EXERCISE TRAINING, SINCE THERE ARE MOLECULAR PROCESSES MEDIATING OXIDATIVE AND NON-OXIDATIVE METABOLISM, ANGIOGENESIS, CARDIAC AND SKELETAL MYOFIBER HYPERTROPHY, AND OTHER PROCESSES THAT LEADS TO A GREATER PHYSIOLOGICAL STATUS. EPIGENETIC IS THE FIELD THAT STUDIES ABOUT GENE EXPRESSION CHANGES HERITABLE BY MEIOSIS AND MITOSIS, BY CHANGES IN CHROMATIN AND DNA CONFORMATION, BUT NOT IN DNA SEQUENCE, THAT STUDIES THE REGULATION ON GENE EXPRESSION THAT IS INDEPENDENT OF GENOTYPE. THE FIELD APPROACHES MECHANISMS OF DNA AND CHROMATIN CONFORMATIONAL CHANGES THAT INHIBIT OR INCREASE GENE EXPRESSION AND DETERMINE TISSUE SPECIFIC PATTERN. THE THREE MAJOR STUDIED EPIGENETIC MECHANISMS ARE DNA METHYLATION, HISTONE MODIFICATION, AND REGULATION OF NONCODING RNA-ASSOCIATED GENES. THIS REVIEW ELUCIDATES THESE MECHANISMS, FOCUSING ON THE RELATIONSHIP BETWEEN THEM AND THEIR RELATIONSHIP WITH EXERCISE TRAINING, PHYSICAL PERFORMANCE AND THE ENHANCEMENT OF HEALTH STATUS. ON THIS CHAPTER, WE CLARIFIED THE RELATIONSHIP OF EPIGENETIC MODULATIONS AND THEIR INTIMAL RELATIONSHIP WITH ACUTE AND CHRONIC EFFECT OF EXERCISE TRAINING, CONCENTRATING OUR EFFORT ON SKELETAL MUSCLE, HEART AND VASCULAR RESPONSES, THAT ARE THE MOST RESPONSIVE SYSTEMS AGAINST TO EXERCISE TRAINING AND PLAY CRUCIAL ROLE ON PHYSICAL PERFORMANCE AND IMPROVEMENT OF HEALTH STATE. 2017 6 5073 21 PHYSICAL EXERCISE PREVENTED STRESS-INDUCED ANXIETY VIA IMPROVING BRAIN RNA METHYLATION. PHYSICAL EXERCISE IS EFFECTIVE IN ALLEVIATING MENTAL DISORDERS BY IMPROVING SYNAPTIC TRANSMISSION; HOWEVER, THE LINK BETWEEN BODY ENDURANCE TRAINING AND NEURAL ADAPTATION HAS NOT YET BEEN COMPLETELY RESOLVED. IN THIS STUDY, THE AUTHORS INVESTIGATED THE ROLE OF RNA N(6) -METHYLADENOSINE (M6A), AN EMERGING EPIGENETIC MECHANISM, IN IMPROVED RESILIENCE AGAINST CHRONIC RESTRAINT STRESS. A COMBINATION OF MOLECULAR, BEHAVIORAL, AND IN VIVO RECORDING DATA DEMONSTRATES EXERCISE-MEDIATED RESTORATION OF M6A IN THE MOUSE MEDIAL PREFRONTAL CORTEX, WHOSE ACTIVITY IS POTENTIATED TO EXERT ANXIOLYTIC EFFECTS. FURTHERMORE, IT IS REVEALED THAT HEPATIC BIOSYNTHESIS OF ONE METHYL DONOR IS NECESSARY FOR EXERCISE TO IMPROVE BRAIN RNA M6A TO COUNTERACT ENVIRONMENTAL STRESS. THIS NOVEL LIVER-BRAIN AXIS PROVIDES AN EXPLANATION FOR BRAIN NETWORK CHANGES UPON EXERCISE TRAINING AND PROVIDES NEW INSIGHTS INTO THE DIAGNOSIS AND TREATMENT OF ANXIETY DISORDERS. 2022 7 4093 29 MATERNAL SEPARATION FOLLOWED BY CHRONIC MILD STRESS IN ADULTHOOD IS ASSOCIATED WITH CONCERTED EPIGENETIC REGULATION OF AP-1 COMPLEX GENES. DEPRESSION IS ONE OF THE MOST PREVALENT MENTAL DISEASES WORLDWIDE. PATIENTS WITH PSYCHIATRIC DISEASES OFTEN HAVE A HISTORY OF CHILDHOOD NEGLECT, INDICATING THAT EARLY-LIFE EXPERIENCES PREDISPOSE TO PSYCHIATRIC DISEASES IN ADULTHOOD. TWO STRONG MODELS WERE USED IN THE PRESENT STUDY: THE MATERNAL SEPARATION/EARLY DEPRIVATION MODEL (MS) AND THE CHRONIC MILD STRESS MODEL (CMS). IN BOTH MODELS, WE FOUND CHANGES IN THE EXPRESSION OF A NUMBER OF GENES SUCH AS CREB AND NPY. STRIKINGLY, THERE WAS A CLEAR REGULATION OF EXPRESSION OF FOUR GENES INVOLVED IN THE AP-1 COMPLEX: C-FOS, C-JUN, FOSB, AND JUN-B. INTERESTINGLY, DIFFERENT EXPRESSION LEVELS WERE OBSERVED DEPENDING ON THE MODEL, WHEREAS THE COMBINATION OF THE MODELS RESULTED IN A NORMAL LEVEL OF GENE EXPRESSION. THE EFFECTS OF MS AND CMS ON GENE EXPRESSION WERE ASSOCIATED WITH DISTINCT HISTONE METHYLATION/ACETYLATION PATTERNS OF ALL FOUR GENES. THE EPIGENETIC CHANGES, LIKE GENE EXPRESSION, WERE ALSO DEPENDENT ON THE SPECIFIC STRESSOR OR THEIR COMBINATION. THE OBTAINED RESULTS SUGGEST THAT SINGLE LIFE EVENTS LEAVE A MARK ON GENE EXPRESSION AND THE EPIGENETIC SIGNATURE OF GENE PROMOTERS, BUT A COMBINATION OF DIFFERENT STRESSORS AT DIFFERENT LIFE STAGES CAN FURTHER CHANGE GENE EXPRESSION THROUGH EPIGENETIC FACTORS, POSSIBLY CAUSING THE LONG-LASTING ADVERSE EFFECTS OF STRESS. 2021 8 3403 20 HOW EPIGENETIC MODIFICATIONS DRIVE THE EXPRESSION AND MEDIATE THE ACTION OF PGC-1ALPHA IN THE REGULATION OF METABOLISM. EPIGENETIC CHANGES ARE A HALLMARK OF SHORT- AND LONG-TERM TRANSCRIPTIONAL REGULATION, AND HENCE INSTRUMENTAL IN THE CONTROL OF CELLULAR IDENTITY AND PLASTICITY. EPIGENETIC MECHANISMS LEADING TO CHANGES IN CHROMATIN STRUCTURE, ACCESSIBILITY FOR RECRUITMENT OF TRANSCRIPTIONAL COMPLEXES, AND INTERACTION OF ENHANCERS AND PROMOTERS ALL CONTRIBUTE TO ACUTE AND CHRONIC ADAPTATIONS OF CELLS, TISSUES AND ORGANS TO INTERNAL AND EXTERNAL PERTURBATIONS. SIMILARLY, THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA COACTIVATOR 1ALPHA (PGC-1ALPHA) IS ACTIVATED BY STIMULI THAT ALTER THE CELLULAR ENERGETIC DEMAND, AND SUBSEQUENTLY CONTROLS COMPLEX TRANSCRIPTIONAL NETWORKS RESPONSIBLE FOR CELLULAR PLASTICITY. IT THUS IS OF NO SURPRISE THAT PGC-1ALPHA IS UNDER THE CONTROL OF EPIGENETIC MECHANISMS, AND CONSTITUTES A MEDIATOR OF EPIGENETIC CHANGES IN VARIOUS TISSUES AND CONTEXTS. IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE LINK BETWEEN EPIGENETICS AND PGC-1ALPHA IN HEALTH AND DISEASE. 2019 9 2360 19 EPIGENETIC REGULATION OF SKELETAL MUSCLE METABOLISM. NORMAL SKELETAL MUSCLE METABOLISM IS ESSENTIAL FOR WHOLE BODY METABOLIC HOMOEOSTASIS AND DISRUPTIONS IN MUSCLE METABOLISM ARE ASSOCIATED WITH A NUMBER OF CHRONIC DISEASES. TRANSCRIPTIONAL CONTROL OF METABOLIC ENZYME EXPRESSION IS A MAJOR REGULATORY MECHANISM FOR MUSCLE METABOLIC PROCESSES. SUBSTANTIAL EVIDENCE IS EMERGING THAT HIGHLIGHTS THE IMPORTANCE OF EPIGENETIC MECHANISMS IN THIS PROCESS. THIS REVIEW WILL EXAMINE THE IMPORTANCE OF EPIGENETICS IN THE REGULATION OF MUSCLE METABOLISM, WITH A PARTICULAR EMPHASIS ON DNA METHYLATION AND HISTONE ACETYLATION AS EPIGENETIC CONTROL POINTS. THE EMERGING CROSS-TALK BETWEEN METABOLISM AND EPIGENETICS IN THE CONTEXT OF HEALTH AND DISEASE WILL ALSO BE EXAMINED. THE CONCEPT OF INHERITANCE OF SKELETAL MUSCLE METABOLIC PHENOTYPES WILL BE DISCUSSED, IN ADDITION TO EMERGING EPIGENETIC THERAPIES THAT COULD BE USED TO ALTER MUSCLE METABOLISM IN CHRONIC DISEASE STATES. 2016 10 2119 25 EPIGENETIC HISTONE MODIFICATION REGULATES DEVELOPMENTAL LEAD EXPOSURE INDUCED HYPERACTIVITY IN RATS. LEAD (PB) EXPOSURE WAS COMMONLY CONSIDERED AS A HIGH ENVIRONMENTAL RISK FACTOR FOR THE DEVELOPMENT OF ATTENTION-DEFICIT/HYPERACTIVITY DISORDER (ADHD). HOWEVER, THE MOLECULAR BASIS OF THIS PATHOLOGICAL PROCESS STILL REMAINS ELUSIVE. IN LIGHT OF THE ROLE OF EPIGENETICS IN MODULATING THE NEUROLOGICAL DISEASE AND THE CAUSATIVE ENVIRONMENT, THE ALTERATIONS OF HISTONE MODIFICATIONS IN THE HIPPOCAMPUS OF RATS EXPOSED BY VARIOUS DOSES OF LEAD, ALONG WITH CONCOMITANT BEHAVIORAL DEFICITS, WERE INVESTIGATED IN THIS STUDY. ACCORDING TO THE FREE AND FORCED OPEN FIELD TEST, THERE SHOWED THAT IN A DOSAGE-DEPENDENT MANNER, LEAD EXPOSURE COULD RESULT IN THE INCREASED LOCOMOTOR ACTIVITY OF RATS, THAT IS, HYPERACTIVITY: A SUBTYPE OF ADHD. WESTERN BLOTTING ASSAYS REVEALED THAT THE LEVELS OF HISTONE ACETYLATION INCREASED SIGNIFICANTLY IN THE HIPPOCAMPUS BY CHRONIC LEAD EXPOSURE, WHILE NO DRAMATIC CHANGES WERE DETECTED IN TERMS OF EXPRESSION YIELDS OF ADHD-RELATED DOPAMINERGIC PROTEINS, INDICATING THAT HISTONE ACETYLATION PLAYS ESSENTIAL ROLES IN THIS TOXICANT-INVOLVED PATHOGENESIS. IN ADDITION, THE INCREASED LEVEL OF HISTONE ACETYLATION MIGHT BE ATTRIBUTED TO THE ENZYMATIC ACTIVITY OF P300, A TYPICAL HISTONE ACETYLTRANSFERASE, AS THE TRANSCRIPTIONAL LEVEL OF P300 WAS SIGNIFICANTLY INCREASED UPON HIGHER-DOSE PB EXPOSURE. IN SUMMARY, THIS STUDY FIRST DISCOVERED THE EPIGENETIC MECHANISM BRIDGING THE ENVIRONMENTAL INFLUENCE (PB) AND THE DISEASE ITSELF (ADHD) IN THE HISTONE MODIFICATION LEVEL, PAVING THE WAY FOR THE COMPREHENSIVE UNDERSTANDING OF ADHD'S ETIOLOGY AND IN FURTHER STEPS, ESTABLISHING THE THERAPY STRATEGY OF THIS WIDESPREAD NEUROLOGICAL DISORDER. 2014 11 5067 27 PHYSICAL ACTIVITY AND DNA METHYLATION IN HUMANS. PHYSICAL ACTIVITY IS A STRONG STIMULUS INFLUENCING THE OVERALL PHYSIOLOGY OF THE HUMAN BODY. EXERCISES LEAD TO BIOCHEMICAL CHANGES IN VARIOUS TISSUES AND EXERT AN IMPACT ON GENE EXPRESSION. EXERCISE-INDUCED CHANGES IN GENE EXPRESSION MAY BE MEDIATED BY EPIGENETIC MODIFICATIONS, WHICH REARRANGE THE CHROMATIN STRUCTURE AND THEREFORE MODULATE ITS ACCESSIBILITY FOR TRANSCRIPTION FACTORS. ONE OF SUCH EPIGENETIC MARK IS DNA METHYLATION THAT INVOLVES AN ATTACHMENT OF A METHYL GROUP TO THE FIFTH CARBON OF CYTOSINE RESIDUE PRESENT IN CG DINUCLEOTIDES (CPG). DNA METHYLATION IS CATALYZED BY A FAMILY OF DNA METHYLTRANSFERASES. THIS REVERSIBLE DNA MODIFICATION RESULTS IN THE RECRUITMENT OF PROTEINS CONTAINING METHYL BINDING DOMAIN AND FURTHER TRANSCRIPTIONAL CO-REPRESSORS LEADING TO THE SILENCING OF GENE EXPRESSION. THE ACCUMULATION OF CPG DINUCLEOTIDES, REFERRED AS CPG ISLANDS, OCCURS AT THE PROMOTER REGIONS IN A GREAT MAJORITY OF HUMAN GENES. THEREFORE, CHANGES IN DNA METHYLATION PROFILE AFFECT THE TRANSCRIPTION OF MULTIPLE GENES. A GROWING BODY OF EVIDENCE INDICATES THAT EXERCISE TRAINING MODULATES DNA METHYLATION IN MUSCLES AND ADIPOSE TISSUE. SOME OF THESE EPIGENETIC MARKERS WERE ASSOCIATED WITH A REDUCED RISK OF CHRONIC DISEASES. THIS REVIEW SUMMARIZES THE CURRENT KNOWLEDGE ABOUT THE INFLUENCE OF PHYSICAL ACTIVITY ON THE DNA METHYLATION STATUS IN HUMANS. 2021 12 2348 28 EPIGENETIC REGULATION OF MUSCLE PHENOTYPE AND ADAPTATION: A POTENTIAL ROLE IN COPD MUSCLE DYSFUNCTION. QUADRICEPS MUSCLE DYSFUNCTION OCCURS IN ONE-THIRD OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IN VERY EARLY STAGES OF THEIR CONDITION, EVEN PRIOR TO THE DEVELOPMENT OF AIRWAY OBSTRUCTION. AMONG SEVERAL FACTORS, DECONDITIONING AND MUSCLE MASS LOSS ARE THE MOST RELEVANT CONTRIBUTING FACTORS LEADING TO THIS DYSFUNCTION. MOREOVER, EPIGENETICS, DEFINED AS THE PROCESS WHEREBY GENE EXPRESSION IS REGULATED BY HERITABLE MECHANISMS THAT DO NOT AFFECT DNA SEQUENCE, COULD BE INVOLVED IN THE SUSCEPTIBILITY TO MUSCLE DYSFUNCTION, PATHOGENESIS, AND PROGRESSION. HEREIN, WE REVIEW THE ROLE OF EPIGENETIC MECHANISMS IN MUSCLE DEVELOPMENT AND ADAPTATION TO ENVIRONMENTAL FACTORS SUCH AS IMMOBILIZATION AND EXERCISE, AND THEIR IMPLICATIONS IN THE PATHOPHYSIOLOGY AND SUSCEPTIBILITY TO MUSCLE DYSFUNCTION IN COPD. THE EPIGENETIC MODIFICATIONS IDENTIFIED SO FAR INCLUDE DNA METHYLATION, HISTONE ACETYLATION AND METHYLATION, AND NON-CODING RNAS SUCH AS MICRORNAS (MIRNAS). IN THE PRESENT REVIEW, WE DESCRIBE THE SPECIFIC CONTRIBUTION OF EPIGENETIC MECHANISMS TO THE REGULATION OF EMBRYONIC MYOGENESIS, MUSCLE STRUCTURE AND METABOLISM, IMMOBILIZATION, AND EXERCISE, AND IN MUSCLES OF COPD PATIENTS. EVENTS RELATED TO MUSCLE DEVELOPMENT AND REGENERATION AND THE RESPONSE TO EXERCISE AND IMMOBILIZATION ARE TIGHTLY REGULATED BY EPIGENETIC MECHANISMS. THESE ENVIRONMENTAL FACTORS PLAY A KEY ROLE IN THE OUTCOME OF MUSCLE MASS AND FUNCTION AS WELL AS IN THE SUSCEPTIBILITY TO MUSCLE DYSFUNCTION IN COPD. FUTURE RESEARCH REMAINS TO BE DONE TO SHED LIGHT ON THE SPECIFIC TARGET PATHWAYS OF MIRNA FUNCTION AND OTHER EPIGENETIC MECHANISMS IN THE SUSCEPTIBILITY, PATHOGENESIS, AND PROGRESSION OF COPD MUSCLE DYSFUNCTION. 2013 13 5645 28 SEX DEPENDENT ALTERATION OF EPIGENETIC MARKS AFTER CHRONIC MORPHINE TREATMENT IN MICE ORGANS. EPIGENETIC MARKS MAY BE ALSO AFFECTED BY SEVERAL FACTORS, SUCH AS AGE, LIFESTYLE, EARLY LIFE EXPERIENCES AND EXPOSURE TO CHEMICALS OR DRUGS, SUCH AS OPIOIDS. PREVIOUS STUDIES HAVE FOCUSED ON HOW MORPHINE EPIGENETICALLY REGULATES DIFFERENT REGIONS OF THE BRAIN THAT ARE IMPLICATED IN TOLERANCE, DEPENDENCE AND OTHER PSYCHIATRIC DISORDERS MORE RELATED TO THE PHYSIO-PATHOLOGICAL EFFECTS OF OPIOIDS. NEVERTHELESS, A SIGNIFICANT KNOWLEDGE GAP REMAINS REGARDING THE EFFECT OF CHRONIC TREATMENT ON OTHER ORGANS AND BIOLOGICAL SYSTEMS. THEREFORE, THE AIM OF THIS WORK IS TO INCREASE OUR KNOWLEDGE ABOUT THE IMPACT OF CHRONIC MORPHINE EXPOSURE ON DNA METHYLATION AND HISTONE MODIFICATION LEVELS IN EACH OF THE ORGANS OF MALE AND FEMALE MODEL MICE IN VIVO. OUR RESULTS REVEAL, FOR THE FIRST TIME, THAT CHRONIC MORPHINE TREATMENT INDUCED CHANGES IN DNA METHYLATION/HYDROXYMETHYLATION AND HISTONE MODIFICATION IN-VIVO AT THE SYSTEMIC LEVEL, REVEALING A POTENTIAL PHYSIOLOGICAL EFFECT ON THE REGULATION OF GENE EXPRESSION. NOTABLY, MORPHINE-INDUCED EPIGENETIC MODIFICATION OCCURS IN A SEX-DEPENDENT MANNER, REVEALING THE EXISTENCE OF DIFFERENT UNDERLYING MECHANISMS OF EPIGENETIC MODIFICATION IN MALE AND FEMALE MICE. 2021 14 5471 28 RESPIRATORY MUSCLE SENESCENCE IN AGEING AND CHRONIC LUNG DISEASES. AGEING IS A PROGRESSIVE CONDITION THAT USUALLY LEADS TO THE LOSS OF PHYSIOLOGICAL PROPERTIES. THIS PROCESS IS ALSO PRESENT IN RESPIRATORY MUSCLES, WHICH ARE AFFECTED BY BOTH SENESCENT CHANGES OCCURRING IN THE WHOLE ORGANISM AND THOSE THAT ARE MORE SPECIFIC FOR MUSCLES. THE MECHANISMS OF THE LATTER CHANGES INCLUDE OXIDATIVE STRESS, DECREASE IN NEUROTROPHIC FACTORS AND DNA ABNORMALITIES. AGEING NORMALLY COEXISTS WITH COMORBIDITIES, INCLUDING RESPIRATORY DISEASES, WHICH FURTHER DETERIORATE THE STRUCTURE AND FUNCTION OF RESPIRATORY MUSCLES. IN THIS CONTEXT, CHANGES INTRINSIC TO AGEING BECOME ENHANCED BY MORE SPECIFIC FACTORS SUCH AS THE IMPAIRMENT IN LUNG MECHANICS AND GAS EXCHANGE, EXACERBATIONS AND HYPOXIA. HYPOXIA IN PARTICULAR HAS A DIRECT EFFECT ON MUSCLES, MAINLY THROUGH THE EXPRESSION OF INDUCIBLE FACTORS (HYPOXIC-INDUCIBLE FACTOR), AND CAN RESULT IN OXIDATIVE STRESS AND CHANGES IN DNA, DECREASE IN MITOCHONDRIAL BIOGENESIS AND DEFECTS IN THE TISSUE REPAIR MECHANISMS. INTENSE EXERCISE CAN ALSO CAUSE DAMAGE IN RESPIRATORY MUSCLES OF ELDERLY RESPIRATORY PATIENTS, BUT THIS CAN BE FOLLOWED BY TISSUE REPAIR AND REMODELLING. HOWEVER, AGEING INTERFERES WITH MUSCLE REPAIR BY TAMPERING WITH THE FUNCTION OF SATELLITE CELLS, MAINLY DUE TO OXIDATIVE STRESS, DNA DAMAGE AND EPIGENETIC MECHANISMS. IN ADDITION TO THE NORMAL PROCESS OF AGEING, STRESS-INDUCED PREMATURE SENESCENCE CAN ALSO OCCUR, INVOLVING CHANGES IN THE EXPRESSION OF MULTIPLE GENES BUT WITHOUT MODIFICATIONS IN TELOMERE LENGTH. 2020 15 3836 27 IONIZING RADIATION POTENTIATES HIGH-FAT DIET-INDUCED INSULIN RESISTANCE AND REPROGRAMS SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS. EXPOSURE TO IONIZING RADIATION INCREASES THE RISK OF CHRONIC METABOLIC DISORDERS SUCH AS INSULIN RESISTANCE AND TYPE 2 DIABETES LATER IN LIFE. WE HYPOTHESIZED THAT IRRADIATION REPROGRAMS THE EPIGENOME OF METABOLIC PROGENITOR CELLS, WHICH COULD ACCOUNT FOR IMPAIRED METABOLISM AFTER CANCER TREATMENT. C57BL/6 MICE WERE TREATED WITH A SINGLE DOSE OF IRRADIATION AND SUBJECTED TO HIGH-FAT DIET (HFD). RNA SEQUENCING AND REDUCED REPRESENTATION BISULFITE SEQUENCING WERE USED TO CREATE TRANSCRIPTOMIC AND EPIGENOMIC PROFILES OF PREADIPOCYTES AND SKELETAL MUSCLE SATELLITE CELLS COLLECTED FROM IRRADIATED MICE. MICE SUBJECTED TO TOTAL BODY IRRADIATION SHOWED ALTERATIONS IN GLUCOSE METABOLISM AND, WHEN CHALLENGED WITH HFD, MARKED HYPERINSULINEMIA. INSULIN SIGNALING WAS CHRONICALLY DISRUPTED IN SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS COLLECTED FROM IRRADIATED MICE AND DIFFERENTIATED IN CULTURE. EPIGENOMIC PROFILING OF SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS FROM IRRADIATED ANIMALS REVEALED SUBSTANTIAL DNA METHYLATION CHANGES, NOTABLY FOR GENES REGULATING THE CELL CYCLE, GLUCOSE/LIPID METABOLISM, AND EXPRESSION OF EPIGENETIC MODIFIERS. OUR RESULTS SHOW THAT TOTAL BODY IRRADIATION ALTERS INTRACELLULAR SIGNALING AND EPIGENETIC PATHWAYS REGULATING CELL PROLIFERATION AND DIFFERENTIATION OF SKELETAL MUSCLE AND ADIPOSE PROGENITOR CELLS AND PROVIDE A POSSIBLE MECHANISM BY WHICH IRRADIATION USED IN CANCER TREATMENT INCREASES THE RISK FOR METABOLIC DISEASE LATER IN LIFE. 2016 16 2711 17 EXERCISE TRAINING ALTERS THE GENOMIC RESPONSE TO ACUTE EXERCISE IN HUMAN ADIPOSE TISSUE. AIM: TO DETERMINE THE GENOMIC MECHANISMS BY WHICH ADIPOSE TISSUE RESPONDS TO ACUTE AND CHRONIC EXERCISE. METHODS: WE PROFILED THE TRANSCRIPTOMIC AND EPIGENETIC RESPONSE TO ACUTE EXERCISE IN HUMAN ADIPOSE TISSUE COLLECTED BEFORE AND AFTER ENDURANCE TRAINING. RESULTS: ALTHOUGH ACUTE EXERCISES WERE PERFORMED AT SAME RELATIVE INTENSITIES, THE MAGNITUDE OF TRANSCRIPTOMIC CHANGES AFTER ACUTE EXERCISE WAS REDUCED BY ENDURANCE TRAINING. DNA METHYLATION REMODELING INDUCED BY ACUTE EXERCISE WAS MORE PROMINENT IN TRAINED VERSUS UNTRAINED STATE. WE FOUND AN OVERLAP BETWEEN GENE EXPRESSION AND DNA METHYLATION CHANGES AFTER ACUTE EXERCISE FOR 32 GENES PRE-TRAINING AND SIX POST-TRAINING, NOTABLY AT ADIPOCYTE-SPECIFIC GENES. CONCLUSION: TRAINING STATUS DIFFERENTIALLY AFFECTS THE EPIGENETIC AND TRANSCRIPTOMIC RESPONSE TO ACUTE EXERCISE IN HUMAN ADIPOSE TISSUE. 2018 17 3604 30 IMPROVEMENT OF PHYSICAL DECLINE THROUGH COMBINED EFFECTS OF MUSCLE ENHANCEMENT AND MITOCHONDRIAL ACTIVATION BY A GASTRIC HORMONE GHRELIN IN MALE 5/6NX CKD MODEL MICE. BECAUSE A PHYSICAL DECLINE CORRELATES WITH AN INCREASED RISK OF A WIDE RANGE OF DISEASE AND MORBIDITY, AN IMPROVEMENT OF PHYSICAL PERFORMANCE IS EXPECTED TO BRING SIGNIFICANT CLINICAL BENEFITS. THE PRIMARY CAUSE OF PHYSICAL DECLINE IN 5/6 NEPHRECTOMIZED (5/6NX) CHRONIC KIDNEY DISEASE MODEL MICE HAS BEEN REGARDED AS A DECREASE IN MUSCLE MASS; HOWEVER, OUR RECENT STUDY SHOWED THAT A DECREASE IN MUSCLE MITOCHONDRIA PLAYS A CRITICAL ROLE. IN THE PRESENT STUDY, WE EXAMINED THE EFFECTS OF A GASTRIC HORMONE GHRELIN, WHICH HAS BEEN REPORTED TO PROMOTE MUSCLE MITOCHONDRIAL OXIDATION, ON THE PHYSICAL DECLINE IN THE CHRONIC KIDNEY DISEASE MODEL MICE, FOCUSING ON THE EPIGENETIC MODULATIONS OF A MITOCHONDRIAL ACTIVATOR GENE, PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA COACTIVATOR-1ALPHA (PGC-1ALPHA). GHRELIN TREATMENT IMPROVED A DECLINE IN EXERCISE ENDURANCE OF 5/6NX MICE, ASSOCIATED WITH AN INCREASE IN BOTH OF THE MUSCLE MASS AND MITOCHONDRIAL AMOUNT. THE EXPRESSION LEVEL OF PGC-1ALPHA WAS DECREASED IN THE SKELETAL MUSCLE OF 5/6NX MICE, WHICH WAS ASSOCIATED WITH AN INCREASE IN THE METHYLATION RATIO OF THE CYTOSINE RESIDUE AT 260 BASE PAIRS UPSTREAM OF THE INITIATION POINT. CONVERSELY, GHRELIN TREATMENT DE-METHYLATED THE CYTOSINE RESIDUE AND INCREASED THE EXPRESSION OF PGC-1ALPHA. A REPRESENTATIVE MUSCLE ANABOLIC FACTOR, IGF-1, DID NOT AFFECT THE EXPRESSION OF PGC-1ALPHA AND MUSCLE MITOCHONDRIAL AMOUNT, ALTHOUGH IT INCREASED MUSCLE MASS. AS A RESULT, IGF-1 TREATMENT IN 5/6NX MICE DID NOT INCREASE THE DECREASED EXERCISE ENDURANCE AS EFFECTIVELY AS GHRELIN TREATMENT DID. THESE FINDINGS INDICATE AN ADVANTAGE OF GHRELIN TREATMENT FOR A RECOVERY OF PHYSICAL DECLINE. 2015 18 5467 34 RESILIENT PHENOTYPE IN CHRONIC MILD STRESS PARADIGM IS ASSOCIATED WITH ALTERED EXPRESSION LEVELS OF MIR-18A-5P AND SEROTONIN 5-HT(1A) RECEPTOR IN DORSAL PART OF THE HIPPOCAMPUS. DISTURBED SEROTONERGIC SIGNALING IN THE HIPPOCAMPUS OBSERVED IN MANY INDIVIDUALS VULNERABLE TO STRESS HAS BEEN SUGGESTED AS ONE OF THE PRIMARY FACTORS CONTRIBUTING TO THE DEVELOPMENT OF DEPRESSION. HOWEVER, LITTLE IS KNOWN ABOUT THE PHYSIOLOGY OF THE BRAIN IN THE RESILIENT PHENOTYPE. RESILIENT SUBJECTS MAINTAIN A POSITIVE MOOD AND PSYCHOLOGICAL BALANCE DESPITE BEING UNDER THE STRESS INFLUENCE. IN OUR STUDY, WE GENERATED STRESS-VULNERABLE AND RESILIENT RATS BY USING A CHRONIC MILD STRESS (CMS) PARADIGM. USING DIFFERENT MOLECULAR APPROACHES, WE REVEALED THAT RESILIENT ANIMALS EXHIBITED A SIGNIFICANTLY DECREASED EXPRESSION LEVEL OF MIR-18A-5P AND, IN THE SAME TIME, AN ELEVATED LEVEL OF 5-HT1AR IN DORSAL, BUT NOT VENTRAL, PART OF THE HIPPOCAMPUS. DESCRIBED BIOCHEMICAL CHANGES WERE NOT OBSERVED IN ANIMALS BEHAVIORALLY VULNERABLE TO STRESS. FURTHER, IN VITRO ANALYSIS SHOWED THAT MIR-18A-5P MAY BE A NEGATIVE EPIGENETIC REGULATOR OF 5-HT1AR SINCE THE TREATMENT OF ADULT HIPPOCAMPAL NEURONS WITH MIR-18A-5P MIMIC SIGNIFICANTLY LOWERED THE EXPRESSION LEVEL OF MRNA ENCODING 5-HT1AR. MOREOVER, BIOINFORMATIC ANALYSIS OF POTENTIAL TARGET GENES EXPRESSED IN THE HIPPOCAMPUS AND BEING REGULATED BY MIR-18A-5P SHOWED THAT THIS MICRORNA MAY REGULATE BIOLOGICAL PROCESSES, SUCH AS AXONOGENESIS, WHICH ARE IMPORTANT IN THE FUNCTIONING OF THE HIPPOCAMPUS IN BOTH RATS AND HUMANS. ALL THESE MOLECULAR FEATURES MAY CONTRIBUTE TO SEROTONERGIC HOMEOSTATIC BALANCE AT THE LEVEL OF SEROTONIN TURNOVER OBSERVED IN HIPPOCAMPI OF RESILIENT BUT NOT STRESS-VULNERABLE RATS. DELINEATION OF FURTHER MOLECULAR AND BIOCHEMICAL MARKERS UNDERLYING RESILIENCE TO STRESS MAY CONTRIBUTE TO THE DEVELOPMENT OF NEW ANTIDEPRESSANT STRATEGIES WHICH WILL RESTORE RESILIENT PHENOTYPE IN DEPRESSED PATIENTS. 2019 19 3292 28 HIGH FAT DIET AND EXERCISE LEAD TO A DISRUPTED AND PATHOGENIC DNA METHYLOME IN MOUSE LIVER. HIGH-FAT DIET CONSUMPTION AND SEDENTARY LIFESTYLE ELEVATES RISK FOR OBESITY, NON-ALCOHOLIC FATTY LIVER DISEASE, AND CANCER. EXERCISE TRAINING CONVEYS HEALTH BENEFITS IN POPULATIONS WITH OR WITHOUT THESE CHRONIC CONDITIONS. DIET AND EXERCISE REGULATE GENE EXPRESSION BY MEDIATING EPIGENETIC MECHANISMS IN MANY TISSUES; HOWEVER, SUCH EFFECTS ARE POORLY DOCUMENTED IN THE LIVER, A CENTRAL METABOLIC ORGAN. TO DISSECT THE CONSEQUENCES OF DIET AND EXERCISE ON THE LIVER EPIGENOME, WE MEASURED DNA METHYLATION, USING REDUCED REPRESENTATION BISULFITE SEQUENCING, AND TRANSCRIPTION, USING RNA-SEQ, IN MICE MAINTAINED ON A FAST FOOD DIET WITH SEDENTARY LIFESTYLE OR EXERCISE, COMPARED WITH CONTROL DIET WITH AND WITHOUT EXERCISE. OUR ANALYSES REVEAL THAT GENOME-WIDE DIFFERENTIAL DNA METHYLATION AND EXPRESSION OF GENE CLUSTERS ARE INDUCED BY DIET AND/OR EXERCISE. A COMBINATION OF FAST FOOD AND EXERCISE TRIGGERS EXTENSIVE GENE ALTERATIONS, WITH ENRICHMENT OF CARBOHYDRATE/LIPID METABOLIC PATHWAYS AND MUSCLE DEVELOPMENTAL PROCESSES. THROUGH EVALUATION OF PUTATIVE PROTECTIVE EFFECTS OF EXERCISE ON DIET-INDUCED DNA METHYLATION, WE SHOW THAT HYPERMETHYLATION IS EFFECTIVELY PREVENTED, ESPECIALLY AT PROMOTERS AND ENHANCERS, WHEREAS HYPOMETHYLATION IS ONLY PARTIALLY ATTENUATED. WE ASSESSED DIET-INDUCED DNA METHYLATION CHANGES ASSOCIATED WITH LIVER CANCER-RELATED EPIGENETIC MODIFICATIONS AND IDENTIFIED SIGNIFICANT INCREASES AT LIVER-SPECIFIC ENHANCERS IN FAST FOOD GROUPS, SUGGESTING PARTIAL LOSS OF LIVER CELL IDENTITY. HYPERMETHYLATION AT A SUBSET OF GENE PROMOTERS WAS ASSOCIATED WITH INHIBITION OF TISSUE DEVELOPMENT AND PROMOTION OF CARCINOGENIC PROCESSES. OUR STUDY DEMONSTRATES EXTENSIVE REPROGRAMMING OF THE EPIGENOME BY DIET AND EXERCISE, EMPHASIZING THE FUNCTIONAL RELEVANCE OF EPIGENETIC MECHANISMS AS AN INTERFACE BETWEEN LIFESTYLE MODIFICATIONS AND PHENOTYPIC ALTERATIONS. 2017 20 2337 23 EPIGENETIC REGULATION OF INFLAMMATORY RESPONSES IN THE CONTEXT OF PHYSICAL ACTIVITY. EPIGENETIC MODIFICATIONS OCCUR IN RESPONSE TO ENVIRONMENTAL CHANGES AND PLAY A FUNDAMENTAL ROLE IN THE REGULATION OF GENE EXPRESSION. PA IS FOUND TO ELICIT AN INFLAMMATORY RESPONSE, BOTH FROM THE INNATE AND ADAPTIVE DIVISIONS OF THE IMMUNOLOGICAL SYSTEM. THE INFLAMMATORY REACTION IS CONSIDERED A VITAL TRIGGER OF EPIGENETIC CHANGES THAT IN TURN MODULATE INFLAMMATORY ACTIONS. THE TISSUE RESPONSES TO PA INVOLVE LOCAL AND GENERAL CHANGES. THE EPIGENETIC MECHANISMS INVOLVED INCLUDE: DNA METHYLATION, HISTONE PROTEINS MODIFICATION AND MICRORNA. ALL OF THEM AFFECT GENETIC EXPRESSION IN AN INFLAMMATORY MILIEU IN PHYSICAL EXERCISE DEPENDING ON THE MAGNITUDE OF PHYSIOLOGICAL STRESS EXPERIENCED BY THE EXERCISER. PA MAY EVOKE ACUTE OR CHRONIC BIOCHEMICAL AND PHYSIOLOGICAL RESPONSES AND HAVE A POSITIVE OR NEGATIVE IMMUNOMODULATORY EFFECT. 2021