1 5334 148 QUADRICEPS MUSCLE WEAKNESS AND ATROPHY ARE ASSOCIATED WITH A DIFFERENTIAL EPIGENETIC PROFILE IN ADVANCED COPD. EPIGENETIC MECHANISMS REGULATE MUSCLE MASS AND FUNCTION IN MODELS OF MUSCLE DYSFUNCTION AND ATROPHY. WE ASSESSED WHETHER QUADRICEPS MUSCLE WEAKNESS AND ATROPHY ARE ASSOCIATED WITH A DIFFERENTIAL EXPRESSION PROFILE OF EPIGENETIC EVENTS IN PATIENTS WITH ADVANCED COPD (CHRONIC OBSTRUCTIVE PULMONARY DISEASE). IN VASTUS LATERALIS (VL) OF SEDENTARY SEVERE COPD PATIENTS (N=41), WHO WERE FURTHER SUBDIVIDED INTO THOSE WITH (N=25) AND WITHOUT (N=16) MUSCLE WEAKNESS AND HEALTHY CONTROLS (N=19), EXPRESSION OF MUSCLE-ENRICHED MIRNAS, HISTONE ACETYLTRANSFERASES (HATS) AND DEACETYLASES (HDACS), GROWTH AND ATROPHY SIGNALLING MARKERS, TOTAL PROTEIN AND HISTONE ACETYLATION, TRANSCRIPTION FACTORS, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE CLINICALLY EVALUATED. COMPARED WITH CONTROLS, IN VL OF ALL COPD TOGETHER AND IN MUSCLE-WEAKNESS PATIENTS, EXPRESSION OF MIR-1, MIR-206 AND MIR-27A, LEVELS OF LYSINE-ACETYLATED PROTEINS AND HISTONES AND ACETYLATED HISTONE 3 WERE INCREASED, WHEREAS EXPRESSION OF HDAC3, HDAC4, SIRTUIN-1 (SIRT-1), IGF-1 (INSULIN-LIKE GROWTH FACTOR-1) WERE DECREASED, AKT (V-AKT MURINE THYMOMA VIRAL ONCOGENE HOMOLOGUE 1) EXPRESSION DID NOT DIFFER, FOLLISTATIN EXPRESSION WAS GREATER, WHEREAS MYOSTATIN EXPRESSION WAS LOWER, SERUM REPONSE FACTOR (SRF) EXPRESSION WAS INCREASED AND FIBRE SIZE OF FAST-TWITCH FIBRES WAS SIGNIFICANTLY REDUCED. IN VL OF SEVERE COPD PATIENTS WITH MUSCLE WEAKNESS AND ATROPHY, EPIGENETIC EVENTS REGULATE MUSCLE DIFFERENTIATION RATHER THAN PROLIFERATION AND MUSCLE GROWTH AND ATROPHY SIGNALLING, PROBABLY AS FEEDBACK MECHANISMS TO PREVENT THOSE MUSCLES FROM UNDERGOING FURTHER ATROPHY. LYSINE-HYPERACETYLATION OF HISTONES MAY DRIVE ENHANCED PROTEIN CATABOLISM IN THOSE MUSCLES. THESE FINDINGS MAY HELP DESIGN NOVEL THERAPEUTIC STRATEGIES (ENHANCERS OF MIRNAS PROMOTING MYOGENESIS AND ACETYLATION INHIBITORS) TO SELECTIVELY TARGET MUSCLE WEAKNESS AND ATROPHY IN SEVERE COPD. 2015 2 1633 71 DO EPIGENETIC EVENTS TAKE PLACE IN THE VASTUS LATERALIS OF PATIENTS WITH MILD CHRONIC OBSTRUCTIVE PULMONARY DISEASE? MUSCLE DYSFUNCTION IS A MAJOR COMORBIDITY IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). SEVERAL BIOLOGICAL MECHANISMS INCLUDING EPIGENETIC EVENTS REGULATE MUSCLE MASS AND FUNCTION IN MODELS OF MUSCLE ATROPHY. INVESTIGATIONS CONDUCTED SO FAR HAVE FOCUSED ON THE ELUCIDATION OF BIOLOGICAL MECHANISMS INVOLVED IN MUSCLE DYSFUNCTION IN ADVANCED COPD. WE ASSESSED WHETHER THE EPIGENETIC PROFILE MAY BE ALTERED IN THE VASTUS LATERALIS OF PATIENTS WITH MILD COPD, NORMAL BODY COMPOSITION, AND MILDLY IMPAIRED MUSCLE FUNCTION AND EXERCISE CAPACITY. IN VASTUS LATERALIS (VL) OF MILD COPD PATIENTS WITH WELL-PRESERVED BODY COMPOSITION AND IN HEALTHY AGE-MATCHED CONTROLS, EXPRESSION OF DNA METHYLATION, MUSCLE-ENRICHED MICRORNAS, HISTONE ACETYLTRANSFERASES (HTAS) AND DEACETYLASES (HDACS), PROTEIN ACETYLATION, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES, AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE CLINICALLY EVALUATED. COMPARED TO HEALTHY CONTROLS, IN THE VL OF MILD COPD PATIENTS, MUSCLE FUNCTION AND EXERCISE CAPACITY WERE MODERATELY REDUCED, DNA METHYLATION LEVELS DID NOT DIFFER, MIR-1 EXPRESSION LEVELS WERE INCREASED AND POSITIVELY CORRELATED WITH BOTH FORCED EXPIRATORY VOLUME IN ONE SECOND (FEV1) AND QUADRICEPS FORCE, HDAC4 PROTEIN LEVELS WERE INCREASED, AND MUSCLE FIBER TYPES AND SIZES WERE NOT DIFFERENT. MODERATE SKELETAL MUSCLE DYSFUNCTION IS A RELEVANT FEATURE IN PATIENTS WITH MILD COPD AND PRESERVED BODY COMPOSITION. SEVERAL EPIGENETIC EVENTS ARE DIFFERENTIALLY EXPRESSED IN THE LIMB MUSCLES OF THESE PATIENTS, PROBABLY AS AN ATTEMPT TO COUNTERBALANCE THE UNDERLYING MECHANISMS THAT ALTER MUSCLE FUNCTION AND MASS. THE STUDY OF PATIENTS AT EARLY STAGES OF THEIR DISEASE IS OF INTEREST AS THEY ARE A TARGET FOR TIMELY THERAPEUTIC INTERVENTIONS THAT MAY SLOW DOWN THE COURSE OF THE DISEASE AND PREVENT THE DELETERIOUS EFFECTS OF MAJOR COMORBIDITIES. 2014 3 350 32 ALTERED DYNAMICS OF LIPID METABOLISM IN MUSCLE CELLS FROM PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHY IS AMELIORATED BY 6 MONTHS OF TRAINING. KEY POINTS: REGULAR EXERCISE IMPROVES MUSCLE FUNCTIONAL CAPACITY AND CLINICAL STATE OF PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHY (IIM). IN OUR STUDY, WE USED AN IN VITRO MODEL OF HUMAN PRIMARY MUSCLE CELL CULTURES, DERIVED FROM IIM PATIENTS BEFORE AND AFTER A 6-MONTH INTENSIVE SUPERVISED TRAINING INTERVENTION TO ASSESS THE IMPACT OF DISEASE AND EXERCISE ON LIPID METABOLISM DYNAMICS. WE PROVIDE EVIDENCE THAT MUSCLE CELLS FROM IIM PATIENTS DISPLAY ALTERED DYNAMICS OF LIPID METABOLISM AND IMPAIRED ADAPTIVE RESPONSE TO SATURATED FATTY ACID LOAD COMPARED TO HEALTHY CONTROLS. A 6-MONTH INTENSIVE SUPERVISED EXERCISE TRAINING INTERVENTION IN PATIENTS WITH IIM MITIGATED DISEASE EFFECTS IN THEIR CULTURED MUSCLE CELLS, IMPROVING OR NORMALIZING THEIR CAPACITY TO HANDLE LIPIDS. THESE FINDINGS HIGHLIGHT THE PUTATIVE ROLE OF INTRINSIC METABOLIC DEFECTS OF SKELETAL MUSCLE IN THE PATHOGENESIS OF IIM AND THE POSITIVE IMPACT OF EXERCISE, MAINTAINED IN VITRO BY YET UNKNOWN EPIGENETIC MECHANISMS. ABSTRACT: EXERCISE IMPROVES SKELETAL MUSCLE FUNCTION, CLINICAL STATE AND QUALITY OF LIFE IN PATIENTS WITH IDIOPATHIC INFLAMMATORY MYOPATHY (IIM). OUR AIM WAS TO IDENTIFY DISEASE-RELATED METABOLIC PERTURBATIONS AND THE IMPACT OF EXERCISE IN SKELETAL MUSCLE CELLS OF IIM PATIENTS. PATIENTS UNDERWENT A 6-MONTH INTENSIVE SUPERVISED TRAINING INTERVENTION. MUSCLE FUNCTION, ANTHROPOMETRIC AND METABOLIC PARAMETERS WERE EXAMINED AND MUSCLE CELL CULTURES WERE ESTABLISHED (M. VASTUS LATERALIS; BERGSTROM NEEDLE BIOPSY) BEFORE AND AFTER TRAINING FROM PATIENTS AND SEDENTARY AGE/SEX/BODY MASS INDEX-MATCHED CONTROLS. [(14) C]PALMITATE WAS USED TO DETERMINE FAT OXIDATION AND LIPID SYNTHESIS (THIN LAYER CHROMATOGRAPHY). CELLS WERE EXPOSED TO A CHRONIC (3 DAYS) AND ACUTE (3 H) METABOLIC CHALLENGE (THE SATURATED FATTY ACID PALMITATE, 100 MUM). REDUCED OXIDATIVE (INTERMEDIATE METABOLITES, -49%, P = 0.034) AND NON-OXIDATIVE (DIGLYCERIDES, -38%, P = 0.013) LIPID METABOLISM WAS IDENTIFIED IN PALMITATE-TREATED MUSCLE CELLS FROM IIM PATIENTS COMPARED TO CONTROLS. THREE DAYS OF PALMITATE EXPOSURE ELICITED DISTINCT REGULATION OF OXIDATIVE PHOSPHORYLATION (OXPHOS) COMPLEX IV AND COMPLEX V/ATP SYNTHASE (P = 0.012/0.005) AND ADIPOSE TRIGLYCERIDE LIPASE IN PATIENTS COMPARED TO CONTROLS (P = 0.045) (IMMUNOBLOTTING). IMPORTANTLY, 6 MONTHS OF TRAINING IN IIM PATIENTS IMPROVED LIPID METABOLISM (CO(2) , P = 0.010; INTERMEDIATE METABOLITES, P = 0.041) AND ACTIVATION OF AMP KINASE (P = 0.007), AND NEARLY NORMALIZED PALMITATE-INDUCED CHANGES IN OXPHOS PROTEINS IN MYOTUBES FROM IIM PATIENTS, IN PARALLEL WITH IMPROVEMENTS OF PATIENTS' CLINICAL STATE. MYOTUBES FROM IIM PATIENTS DISPLAYED ALTERED DYNAMICS OF LIPID METABOLISM AND IMPAIRED RESPONSE TO METABOLIC CHALLENGE WITH SATURATED FATTY ACID. OUR OBSERVATIONS SUGGEST THAT METABOLIC DEFECTS INTRINSIC TO SKELETAL MUSCLE COULD REPRESENT NON-IMMUNE PATHOMECHANISMS, WHICH CAN CONTRIBUTE TO MUSCLE WEAKNESS IN IIM. A 6-MONTH TRAINING INTERVENTION MITIGATED DISEASE EFFECTS IN MUSCLE CELLS IN VITRO, INDICATING THE EXISTENCE OF EPIGENETIC REGULATORY MECHANISMS. 2021 4 4253 21 METHYLOME OF HUMAN SKELETAL MUSCLE AFTER ACUTE & CHRONIC RESISTANCE EXERCISE TRAINING, DETRAINING & RETRAINING. DNA METHYLATION IS AN IMPORTANT EPIGENETIC MODIFICATION THAT CAN REGULATE GENE EXPRESSION FOLLOWING ENVIRONMENTAL ENCOUNTERS WITHOUT CHANGES TO THE GENETIC CODE. USING INFINIUM METHYLATIONEPIC BEADCHIP ARRAYS (850,000 CPG SITES) WE ANALYSED FOR THE FIRST TIME, DNA ISOLATED FROM UNTRAINED HUMAN SKELETAL MUSCLE BIOPSIES (VASTUS LATERALIS) AT BASELINE (REST) AND IMMEDIATELY FOLLOWING AN ACUTE (SINGLE) BOUT OF RESISTANCE EXERCISE. IN THE SAME PARTICIPANTS, WE ALSO ANALYSED THE METHYLOME FOLLOWING A PERIOD OF MUSCLE GROWTH (HYPERTROPHY) EVOKED VIA CHRONIC (REPEATED BOUTS-3 SESSIONS/WK) RESISTANCE EXERCISE (RE) (TRAINING) OVER 7-WEEKS, FOLLOWED BY COMPLETE EXERCISE CESSATION FOR 7-WEEKS RETURNING MUSCLE BACK TO BASELINE LEVELS (DETRAINING), AND FINALLY FOLLOWED BY A SUBSEQUENT 7-WEEK PERIOD OF RE-INDUCED HYPERTROPHY (RETRAINING). THESE VALUABLE METHYLOME DATA SETS DESCRIBED IN THE PRESENT MANUSCRIPT AND DEPOSITED IN AN OPEN-ACCESS REPOSITORY CAN NOW BE SHARED AND RE-USED TO ENABLE THE IDENTIFICATION OF EPIGENETICALLY REGULATED GENES/NETWORKS THAT ARE MODIFIED AFTER ACUTE ANABOLIC STIMULI AND HYPERTROPHY, AND FURTHER INVESTIGATE THE PHENOMENON OF EPIGENETIC MEMORY IN SKELETAL MUSCLE. 2018 5 2170 69 EPIGENETIC MECHANISMS IN RESPIRATORY MUSCLE DYSFUNCTION OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE. EPIGENETIC EVENTS ARE DIFFERENTIALLY EXPRESSED IN THE LUNGS AND AIRWAYS OF PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). MOREOVER, EPIGENETIC MECHANISMS ARE INVOLVED IN THE SKELETAL (PERIPHERAL) MUSCLE DYSFUNCTION OF COPD PATIENTS. WHETHER EPIGENETIC EVENTS MAY ALSO REGULATE RESPIRATORY MUSCLE DYSFUNCTION IN COPD REMAINS UNKNOWN. WE HYPOTHESIZED THAT EPIGENETIC MECHANISMS WOULD BE DIFFERENTIALLY EXPRESSED IN THE MAIN INSPIRATORY MUSCLE (DIAPHRAGM) OF PATIENTS WITH COPD OF A WIDE RANGE OF DISEASE SEVERITY COMPARED TO HEALTHY CONTROLS. IN DIAPHRAGM MUSCLE SPECIMENS (THORACOTOMY DUE TO LUNG LOCALIZED NEOPLASMS) OF SEDENTARY PATIENTS WITH MILD-TO-MODERATE AND SEVERE COPD, WITH PRESERVED BODY COMPOSITION, AND SEDENTARY HEALTHY CONTROLS, EXPRESSION OF MUSCLE-ENRICHED MICRORNAS, HISTONE ACETYLTRANSFERASES (HATS) AND DEACETYLASES (HDACS), TOTAL DNA METHYLATION AND PROTEIN ACETYLATION, SMALL UBIQUITIN-RELATED MODIFIER (SUMO) LIGASES, MUSCLE-SPECIFIC TRANSCRIPTION FACTORS, AND MUSCLE STRUCTURE WERE EXPLORED. ALL SUBJECTS WERE ALSO CLINICALLY EVALUATED: LUNG AND MUSCLE FUNCTIONS AND EXERCISE CAPACITY. COMPARED TO HEALTHY CONTROLS, PATIENTS EXHIBITED MODERATE AIRFLOW LIMITATION AND DIFFUSION CAPACITY, AND REDUCED EXERCISE TOLERANCE AND TRANSDIAPHRAGMATIC STRENGTH. MOREOVER, IN THE DIAPHRAGM OF THE COPD PATIENTS, MUSCLE-SPECIFIC MICRORNA EXPRESSION WAS DOWNREGULATED, WHILE HDAC4 AND MYOCYTE ENHANCER FACTOR (MEF)2C PROTEIN LEVELS WERE HIGHER, AND DNA METHYLATION LEVELS, MUSCLE FIBER TYPES AND SIZES DID NOT DIFFER BETWEEN PATIENTS AND CONTROLS. IN THE MAIN RESPIRATORY MUSCLE OF COPD PATIENTS WITH A WIDE RANGE OF DISEASE SEVERITY AND NORMAL BODY COMPOSITION, MUSCLE-SPECIFIC MICRORNAS WERE DOWNREGULATED, WHILE HDAC4 AND MEF2C LEVELS WERE UPREGULATED. IT IS LIKELY THAT THESE EPIGENETIC EVENTS ACT AS BIOLOGICAL ADAPTIVE MECHANISMS TO BETTER OVERCOME THE CONTINUOUS INSPIRATORY LOADS OF THE RESPIRATORY SYSTEM IN COPD. THESE FINDINGS MAY OFFER NOVEL THERAPEUTIC STRATEGIES TO SPECIFICALLY TARGET RESPIRATORY MUSCLE DYSFUNCTION IN PATIENTS WITH COPD. 2014 6 4577 33 MYOSTATIN: BASIC BIOLOGY TO CLINICAL APPLICATION. MYOSTATIN IS A MEMBER OF THE TRANSFORMING GROWTH FACTOR (TGF)-BETA SUPERFAMILY. IT IS EXPRESSED BY ANIMAL AND HUMAN SKELETAL MUSCLE CELLS WHERE IT LIMITS MUSCLE GROWTH AND PROMOTES PROTEIN BREAKDOWN. ITS EFFECTS ARE INFLUENCED BY COMPLEX MECHANISMS INCLUDING TRANSCRIPTIONAL AND EPIGENETIC REGULATION AND MODULATION BY EXTRACELLULAR BINDING PROTEINS. DUE TO ITS ACTIONS IN PROMOTING MUSCLE ATROPHY AND CACHEXIA, MYOSTATIN HAS BEEN INVESTIGATED AS A PROMISING THERAPEUTIC TARGET TO COUNTERACT MUSCLE MASS LOSS IN EXPERIMENTAL MODELS AND PATIENTS AFFECTED BY DIFFERENT MUSCLE-WASTING CONDITIONS. MOREOVER, GROWING EVIDENCE INDICATES THAT MYOSTATIN, BEYOND TO REGULATE SKELETAL MUSCLE GROWTH, MAY HAVE A ROLE IN MANY PHYSIOLOGIC AND PATHOLOGIC PROCESSES, SUCH AS OBESITY, INSULIN RESISTANCE, CARDIOVASCULAR AND CHRONIC KIDNEY DISEASE. IN THIS CHAPTER, WE REVIEW MYOSTATIN BIOLOGY, INCLUDING INTRACELLULAR AND EXTRACELLULAR REGULATORY PATHWAYS, AND THE ROLE OF MYOSTATIN IN MODULATING PHYSIOLOGIC PROCESSES, SUCH AS MUSCLE GROWTH AND AGING. MOREOVER, WE DISCUSS THE MOST RELEVANT EXPERIMENTAL AND CLINICAL EVIDENCE SUPPORTING THE EXTRA-MUSCLE EFFECTS OF MYOSTATIN. FINALLY, WE CONSIDER THE MAIN STRATEGIES DEVELOPED AND TESTED TO INHIBIT MYOSTATIN IN CLINICAL TRIALS AND DISCUSS THE LIMITS AND FUTURE PERSPECTIVES OF THE RESEARCH ON MYOSTATIN. 2022 7 2505 37 EPIGENETICS AND MUSCLE DYSFUNCTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMMON, PREVENTABLE, AND TREATABLE DISEASE AND A MAJOR LEADING CAUSE OF MORBIDITY AND MORTALITY WORLDWIDE. IN COPD, COMORBIDITIES, ACUTE EXACERBATIONS, AND SYSTEMIC MANIFESTATIONS NEGATIVELY INFLUENCE DISEASE SEVERITY AND PROGRESSION REGARDLESS OF THE RESPIRATORY CONDITION. SKELETAL MUSCLE DYSFUNCTION, WHICH IS ONE OF THE COMMONEST SYSTEMIC MANIFESTATIONS IN PATIENTS WITH COPD, HAS A TREMENDOUS IMPACT ON THEIR EXERCISE CAPACITY AND QUALITY OF LIFE. SEVERAL PATHOPHYSIOLOGICAL AND MOLECULAR UNDERLYING MECHANISMS INCLUDING EPIGENETICS (THE PROCESS WHEREBY GENE EXPRESSION IS REGULATED BY HERITABLE MECHANISMS THAT DO NOT AFFECT DNA SEQUENCE) HAVE BEEN SHOWN TO PARTICIPATE IN THE ETIOLOGY OF COPD MUSCLE DYSFUNCTION. THE EPIGENETIC MODIFICATIONS IDENTIFIED SO FAR IN CELLS INCLUDE DNA METHYLATION, HISTONE ACETYLATION AND METHYLATION, AND NONCODING RNAS SUCH AS MICRORNAS. HEREIN, WE FIRST REVIEW THE ROLE OF EPIGENETIC MECHANISMS IN MUSCLE DEVELOPMENT AND ADAPTATION TO ENVIRONMENTAL FACTORS IN SEVERAL MODELS. MOREOVER, THE EPIGENETIC EVENTS REPORTED SO FAR TO BE POTENTIALLY INVOLVED IN MUSCLE DYSFUNCTION AND MASS LOSS OF PATIENTS WITH COPD ARE ALSO DISCUSSED. FURTHERMORE, THE DIFFERENT EXPRESSION PROFILE OF SEVERAL MUSCLE-ENRICHED MICRORNAS IN THE DIAPHRAGM AND VASTUS LATERALIS MUSCLES OF PATIENTS WITH COPD ARE ALSO REVIEWED FROM RESULTS RECENTLY OBTAINED IN OUR GROUP. THE ROLE OF PROTEIN HYPERACETYLATION IN ENHANCED MUSCLE PROTEIN CATABOLISM OF LIMB MUSCLES IS ALSO DISCUSSED. FUTURE RESEARCH SHOULD FOCUS ON THE FULL ELUCIDATION OF THE TRIGGERS OF EPIGENETIC MECHANISMS AND THEIR SPECIFIC DOWNSTREAM BIOLOGICAL PATHWAYS IN COPD MUSCLE DYSFUNCTION AND WASTING. 2015 8 5679 43 SHORT- AND LONG-TERM HINDLIMB IMMOBILIZATION AND RELOADING: PROFILE OF EPIGENETIC EVENTS IN GASTROCNEMIUS. SKELETAL MUSCLE DYSFUNCTION AND ATROPHY ARE CHARACTERISTIC FEATURES ACCOMPANYING CHRONIC CONDITIONS. EPIGENETIC EVENTS REGULATE MUSCLE MASS AND FUNCTION MAINTENANCE. WE HYPOTHESIZED THAT THE PATTERN OF EPIGENETIC EVENTS (MUSCLE-ENRICHED MICRORNAS AND HISTONE ACETYLATION) AND ACETYLATION OF TRANSCRIPTION FACTORS KNOWN TO SIGNAL MUSCLE WASTING MAY DIFFER BETWEEN EARLY- AND LATE-TIME POINTS IN SKELETAL MUSCLES OF MICE EXPOSED TO HINDLIMB IMMOBILIZATION (I) AND RECOVERY FOLLOWING I. BODY AND MUSCLE WEIGHTS, GRIP STRENGTH, MUSCLE-ENRICHED MICRORNAS, HISTONE DEACETYLASES (HDACS), ACETYLATION OF PROTEINS, HISTONES, AND TRANSCRIPTION FACTORS (TF), MYOGENIC TF FACTORS, AND MUSCLE PHENOTYPE WERE ASSESSED IN GASTROCNEMIUS OF MICE EXPOSED TO PERIODS (1, 2, 3, 7, 15, AND 30 DAYS, I GROUPS) OF HINDLIMB IMMOBILIZATION, AND IN THOSE EXPOSED TO RELOADING FOR DIFFERENT PERIODS OF TIME (1, 3, 7, 15, AND 30 DAYS, R GROUPS) FOLLOWING 7-DAY IMMOBILIZATION. COMPARED TO NON-IMMOBILIZED CONTROLS, MUSCLE WEIGHT, LIMB STRENGTH, MICRORNAS, ESPECIALLY MIR-486, SIRT1 LEVELS, AND SLOW- AND FAST-TWITCH CROSS-SECTIONAL AREAS WERE DECREASED IN MICE OF I GROUPS, WHEREAS PAX7 AND ACETYLATED FOXO1 AND FOXO3 LEVELS WERE INCREASED. MUSCLE RELOADING FOLLOWING SPLINT REMOVAL IMPROVED MUSCLE MASS LOSS, STRENGTH, AND FIBER ATROPHY, BY INCREASING MICRORNAS, PARTICULARLY MIR-486, AND SIRT1 CONTENT, WHILE DECREASING ACETYLATED FOXO1 AND FOXO3 LEVELS. IN THIS MOUSE MODEL OF DISUSE MUSCLE ATROPHY, MUSCLE-ENRICHED MICRORNAS, ESPECIALLY MIR-486, THROUGH PAX7 REGULATION DELAYED MUSCLE CELL DIFFERENTIATION FOLLOWING UNLOADING OF GASTROCNEMIUS MUSCLE. ACETYLATION OF FOXO1 AND 3 SEEMED TO DRIVE MUSCLE MASS LOSS AND ATROPHY, WHILE DEACETYLATION OF THESE FACTORS THROUGH SIRT1 WOULD ENABLE THE MUSCLE FIBERS TO REGENERATE. J. CELL. PHYSIOL. 232: 1415-1427, 2017. (C) 2016 WILEY PERIODICALS, INC. 2017 9 4543 31 MUSCLE DYSFUNCTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE: UPDATE ON CAUSES AND BIOLOGICAL FINDINGS. RESPIRATORY AND/OR LIMB MUSCLE DYSFUNCTION, WHICH ARE FREQUENTLY OBSERVED IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS, CONTRIBUTE TO THEIR DISEASE PROGNOSIS IRRESPECTIVE OF THE LUNG FUNCTION. MUSCLE DYSFUNCTION IS CAUSED BY THE INTERACTION OF LOCAL AND SYSTEMIC FACTORS. THE KEY DELETERIOUS ETIOLOGIC FACTORS ARE PULMONARY HYPERINFLATION FOR THE RESPIRATORY MUSCLES AND DECONDITIONING SECONDARY TO REDUCED PHYSICAL ACTIVITY FOR LIMB MUSCLES. NONETHELESS, CIGARETTE SMOKE, SYSTEMIC INFLAMMATION, NUTRITIONAL ABNORMALITIES, EXERCISE, EXACERBATIONS, ANABOLIC INSUFFICIENCY, DRUGS AND COMORBIDITIES ALSO SEEM TO PLAY A RELEVANT ROLE. ALL THESE FACTORS MODIFY THE PHENOTYPE OF THE MUSCLES, THROUGH THE INDUCTION OF SEVERAL BIOLOGICAL PHENOMENA IN PATIENTS WITH COPD. WHILE RESPIRATORY MUSCLES IMPROVE THEIR AEROBIC PHENOTYPE (PERCENTAGE OF OXIDATIVE FIBERS, CAPILLARIZATION, MITOCHONDRIAL DENSITY, ENZYME ACTIVITY IN THE AEROBIC PATHWAYS, ETC.), LIMB MUSCLES EXHIBIT THE OPPOSITE PHENOTYPE. IN ADDITION, BOTH MUSCLE GROUPS SHOW OXIDATIVE STRESS, SIGNS OF DAMAGE AND EPIGENETIC CHANGES. HOWEVER, FIBER ATROPHY, INCREASED NUMBER OF INFLAMMATORY CELLS, ALTERED REGENERATIVE CAPACITY; SIGNS OF APOPTOSIS AND AUTOPHAGY, AND AN IMBALANCE BETWEEN PROTEIN SYNTHESIS AND BREAKDOWN ARE RATHER CHARACTERISTIC FEATURES OF THE LIMB MUSCLES, MOSTLY IN PATIENTS WITH REDUCED BODY WEIGHT. DESPITE THAT SIGNIFICANT PROGRESS HAS BEEN ACHIEVED IN THE LAST DECADES, FULL ELUCIDATION OF THE SPECIFIC ROLES OF THE TARGET BIOLOGICAL MECHANISMS INVOLVED IN COPD MUSCLE DYSFUNCTION IS STILL REQUIRED. SUCH AN ACHIEVEMENT WILL BE CRUCIAL TO ADEQUATELY TACKLE WITH THIS RELEVANT CLINICAL PROBLEM OF COPD PATIENTS IN THE NEAR-FUTURE. 2015 10 169 32 ABNORMALITIES OF AMPK ACTIVATION AND GLUCOSE UPTAKE IN CULTURED SKELETAL MUSCLE CELLS FROM INDIVIDUALS WITH CHRONIC FATIGUE SYNDROME. BACKGROUND: POST EXERTIONAL MUSCLE FATIGUE IS A KEY FEATURE IN CHRONIC FATIGUE SYNDROME (CFS). ABNORMALITIES OF SKELETAL MUSCLE FUNCTION HAVE BEEN IDENTIFIED IN SOME BUT NOT ALL PATIENTS WITH CFS. TO TRY TO LIMIT POTENTIAL CONFOUNDERS THAT MIGHT CONTRIBUTE TO THIS CLINICAL HETEROGENEITY, WE DEVELOPED A NOVEL IN VITRO SYSTEM THAT ALLOWS COMPARISON OF AMP KINASE (AMPK) ACTIVATION AND METABOLIC RESPONSES TO EXERCISE IN CULTURED SKELETAL MUSCLE CELLS FROM CFS PATIENTS AND CONTROL SUBJECTS. METHODS: SKELETAL MUSCLE CELL CULTURES WERE ESTABLISHED FROM 10 SUBJECTS WITH CFS AND 7 AGE-MATCHED CONTROLS, SUBJECTED TO ELECTRICAL PULSE STIMULATION (EPS) FOR UP TO 24H AND EXAMINED FOR CHANGES ASSOCIATED WITH EXERCISE. RESULTS: IN THE BASAL STATE, CFS CULTURES SHOWED INCREASED MYOGENIN EXPRESSION BUT DECREASED IL6 SECRETION DURING DIFFERENTIATION COMPARED WITH CONTROL CULTURES. CONTROL CULTURES SUBJECTED TO 16 H EPS SHOWED A SIGNIFICANT INCREASE IN BOTH AMPK PHOSPHORYLATION AND GLUCOSE UPTAKE COMPARED WITH UNSTIMULATED CELLS. IN CONTRAST, CFS CULTURES SHOWED NO INCREASE IN AMPK PHOSPHORYLATION OR GLUCOSE UPTAKE AFTER 16 H EPS. HOWEVER, GLUCOSE UPTAKE REMAINED RESPONSIVE TO INSULIN IN THE CFS CELLS POINTING TO AN EXERCISE-RELATED DEFECT. IL6 SECRETION IN RESPONSE TO EPS WAS SIGNIFICANTLY REDUCED IN CFS COMPARED WITH CONTROL CULTURES AT ALL TIME POINTS MEASURED. CONCLUSION: EPS IS AN EFFECTIVE MODEL FOR ELICITING MUSCLE CONTRACTION AND THE METABOLIC CHANGES ASSOCIATED WITH EXERCISE IN CULTURED SKELETAL MUSCLE CELLS. WE FOUND FOUR MAIN DIFFERENCES IN CULTURED SKELETAL MUSCLE CELLS FROM SUBJECTS WITH CFS; INCREASED MYOGENIN EXPRESSION IN THE BASAL STATE, IMPAIRED ACTIVATION OF AMPK, IMPAIRED STIMULATION OF GLUCOSE UPTAKE AND DIMINISHED RELEASE OF IL6. THE RETENTION OF THESE DIFFERENCES IN CULTURED MUSCLE CELLS FROM CFS SUBJECTS POINTS TO A GENETIC/EPIGENETIC MECHANISM, AND PROVIDES A SYSTEM TO IDENTIFY NOVEL THERAPEUTIC TARGETS. 2015 11 4841 37 ONE WEEK, BUT NOT 12 HOURS, OF CAST IMMOBILIZATION ALTERS PROMOTOR DNA METHYLATION PATTERNS IN THE NNOS GENE IN MOUSE SKELETAL MUSCLE. KEY POINTS: DNA METHYLATION MAY PLAY AN IMPORTANT ROLE IN REGULATING GENE EXPRESSION IN SKELETAL MUSCLE TO ADAPT TO PHYSICAL ACTIVITY AND INACTIVITY. NEURONAL NITRIC OXIDE SYNTHASE (NNOS) IN SKELETAL MUSCLE IS A KEY REGULATOR OF SKELETAL MUSCLE MASS; HOWEVER, IT IS UNCLEAR WHETHER NNOS EXPRESSION IS REGULATED BY DNA METHYLATION. WE FOUND THAT 1 WEEK OF CAST IMMOBILIZATION INCREASED NNOS DNA METHYLATION LEVELS AND DOWNREGULATED NNOS GENE EXPRESSION IN ATROPHIC SLOW-TWITCH SOLEUS MUSCLE FROM THE MOUSE LEG. THESE CHANGES WERE NOT DETECTED IN NON-ATROPHIC FAST-TWITCH EXTENSOR DIGITORUM LONGUS MUSCLE. TWELVE HOURS OF CAST IMMOBILIZATION DECREASED NNOS GENE EXPRESSION, WHEREAS NNOS DNA METHYLATION LEVELS WERE UNCHANGED, SUGGESTING THAT DOWNREGULATION OF NNOS GENE EXPRESSION BY SHORT-TERM MUSCLE INACTIVITY IS INDEPENDENT OF THE DNA METHYLATION PATTERN. THESE FINDINGS CONTRIBUTE TO A BETTER UNDERSTANDING OF THE MAINTENANCE OF SKELETAL MUSCLE MASS AND PREVENTION OF MUSCLE ATROPHY BY EPIGENETIC MECHANISMS VIA THE NNOS/NO PATHWAY. ABSTRACT: DNA METHYLATION IS A MECHANISM THAT CONTROLS GENE EXPRESSION IN SKELETAL MUSCLE UNDER VARIOUS ENVIRONMENTAL STIMULI, SUCH AS PHYSICAL ACTIVITY AND INACTIVITY. NEURONAL NITRIC OXIDE SYNTHASE (NNOS) REGULATES MUSCLE ATROPHY IN SKELETAL MUSCLE. HOWEVER, THE MECHANISMS REGULATING NNOS EXPRESSION IN ATROPHIC MUSCLE REMAIN UNCLEAR. WE HYPOTHESIZED THAT NNOS EXPRESSION IN ATROPHIC MUSCLE IS REGULATED BY DNA METHYLATION OF THE NNOS PROMOTOR IN SOLEUS (SOL; SLOW-TWITCH FIBRE DOMINANT) AND EXTENSOR DIGITORUM LONGUS (EDL; FAST-TWITCH FIBRE DOMINANT) MUSCLES. ONE WEEK OF CAST IMMOBILIZATION INDUCED SIGNIFICANT MUSCLE ATROPHY IN SOL BUT NOT IN EDL. WE SHOWED THAT 1 WEEK OF CAST IMMOBILIZATION INCREASED NNOS DNA METHYLATION LEVELS IN SOL, ALTHOUGH ONLY A MINOR CHANGE WAS DETECTED IN EDL. CONSISTENT WITH THE INCREASED DNA METHYLATION LEVELS IN ATROPHIC SOL, THE GENE EXPRESSION LEVELS OF TOTAL NNOS AND NNOSMICRO (I.E. THE MAJOR SPLICING VARIANT OF NNOS IN SKELETAL MUSCLE) DECREASED. THE ABUNDANCE OF THE NNOS PROTEIN AND CELL MEMBRANE (ESPECIALLY TYPE IIA FIBRE) IMMUNOREACTIVITY ALSO DECREASED IN ATROPHIC SOL. THESE CHANGES WERE NOT OBSERVED IN EDL AFTER 1 WEEK OF CAST IMMOBILIZATION. FURTHERMORE, DESPITE THE LACK OF SIGNIFICANT ATROPHY, 12 H OF CAST IMMOBILIZATION DECREASED GENE EXPRESSION LEVELS OF TOTAL NNOS AND NNOSMICRO IN SOL. HOWEVER, NO ASSOCIATION WAS DETECTED BETWEEN NNOS DNA METHYLATION AND GENE EXPRESSION. THE EXPRESSION OF THE NNOSBETA GENE, ANOTHER SPLICING VARIANT OF NNOS, IN EDL WAS UNCHANGED BY CAST IMMOBILIZATION, WHEREAS ITS EXPRESSION WAS NOT DETECTED IN SOL. WE CONCLUDED THAT CHRONIC ADAPTATION OF NNOS GENE EXPRESSION IN CAST IMMOBILIZED MUSCLE MAY INVOLVE NNOS DNA METHYLATION. 2019 12 5327 28 PULSED GLUCOCORTICOIDS ENHANCE DYSTROPHIC MUSCLE PERFORMANCE THROUGH EPIGENETIC-METABOLIC REPROGRAMMING. IN HUMANS, CHRONIC GLUCOCORTICOID USE IS ASSOCIATED WITH SIDE EFFECTS LIKE MUSCLE WASTING, OBESITY, AND METABOLIC SYNDROME. INTERMITTENT STEROID DOSING HAS BEEN PROPOSED IN DUCHENNE MUSCULAR DYSTROPHY PATIENTS TO MITIGATE THE SIDE EFFECTS SEEN WITH DAILY STEROID INTAKE. WE EVALUATED BIOMARKERS FROM DUCHENNE MUSCULAR DYSTROPHY PATIENTS, FINDING THAT, COMPARED WITH CHRONIC DAILY STEROID USE, WEEKEND STEROID USE WAS ASSOCIATED WITH REDUCED SERUM INSULIN, FREE FATTY ACIDS, AND BRANCHED CHAIN AMINO ACIDS, AS WELL AS REDUCTION IN FAT MASS DESPITE HAVING SIMILAR BMIS. WE REASONED THAT INTERMITTENT PREDNISONE ADMINISTRATION IN DYSTROPHIC MICE WOULD ALTER MUSCLE EPIGENOMIC SIGNATURES, AND WE IDENTIFIED THE COORDINATED ACTION OF THE GLUCOCORTICOID RECEPTOR, KLF15 AND MEF2C AS MEDIATORS OF A GENE EXPRESSION PROGRAM DRIVING METABOLIC REPROGRAMMING AND ENHANCED NUTRIENT UTILIZATION. MUSCLE LACKING KLF15 FAILED TO RESPOND TO INTERMITTENT STEROIDS. FURTHERMORE, COADMINISTRATION OF THE HISTONE ACETYLTRANSFERASE INHIBITOR ANACARDIC ACID WITH STEROIDS IN MDX MICE ELIMINATED STEROID-SPECIFIC EPIGENETIC MARKS AND ABROGATED THE STEROID RESPONSE. TOGETHER, THESE FINDINGS INDICATE THAT INTERMITTENT, REPEATED EXPOSURE TO GLUCOCORTICOIDS PROMOTES PERFORMANCE IN DYSTROPHIC MUSCLE THROUGH AN EPIGENETIC PROGRAM THAT ENHANCES NUTRIENT UTILIZATION. 2019 13 4410 36 MOLECULAR AND BIOLOGICAL PATHWAYS OF SKELETAL MUSCLE DYSFUNCTION IN CHRONIC OBSTRUCTIVE PULMONARY DISEASE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) WILL BE A MAJOR LEADING CAUSE OF DEATH WORLDWIDE IN THE NEAR FUTURE. WEAKNESS AND ATROPHY OF THE QUADRICEPS ARE ASSOCIATED WITH A SIGNIFICANTLY POORER PROGNOSIS AND INCREASED MORTALITY IN COPD. DESPITE THAT SKELETAL MUSCLE DYSFUNCTION MAY AFFECT BOTH RESPIRATORY AND LIMB MUSCLE GROUPS IN COPD, THE LATTER ARE FREQUENTLY MORE SEVERELY AFFECTED. THEREFORE, MUSCLE DYSFUNCTION IN COPD IS A COMMON SYSTEMIC MANIFESTATION THAT SHOULD BE EVALUATED ON ROUTINE BASIS IN CLINICAL SETTINGS. IN THE PRESENT REVIEW, SEVERAL ASPECTS OF COPD MUSCLE DYSFUNCTION ARE BEING REVIEWED, WITH SPECIAL EMPHASIS ON THE UNDERLYING BIOLOGICAL MECHANISMS. FIGURES ON THE PREVALENCE OF COPD MUSCLE DYSFUNCTION AND THE MOST RELEVANT ETIOLOGIC CONTRIBUTORS ARE ALSO PROVIDED. DESPITE THAT ONGOING RESEARCH WILL SHED LIGHT INTO THE CONTRIBUTION OF ADDITIONAL MECHANISMS TO COPD MUSCLE DYSFUNCTION, CURRENT KNOWLEDGE POINTS TOWARD THE INVOLVEMENT OF A WIDE SPECTRUM OF CELLULAR AND MOLECULAR EVENTS THAT ARE DIFFERENTIALLY EXPRESSED IN RESPIRATORY AND LIMB MUSCLES. SUCH MECHANISMS ARE THOROUGHLY DESCRIBED IN THE ARTICLE. THE CONTRIBUTION OF EPIGENETIC EVENTS ON COPD MUSCLE DYSFUNCTION IS ALSO REVIEWED. WE CONCLUDE THAT IN VIEW OF THE LATEST DISCOVERIES, FROM NOW, ON NEW AVENUES OF RESEARCH SHOULD BE DESIGNED TO SPECIFICALLY TARGET CELLULAR MECHANISMS AND PATHWAYS THAT IMPAIR MUSCLE MASS AND FUNCTION IN COPD USING PHARMACOLOGICAL STRATEGIES AND/OR EXERCISE TRAINING MODALITIES. 2016 14 2940 33 GENETIC AND EPIGENETIC ALTERATIONS IN NORMAL AND SENSITIVE COPD-DISEASED HUMAN BRONCHIAL EPITHELIAL CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5). EVEN THOUGH CLINICAL, EPIDEMIOLOGICAL AND TOXICOLOGICAL STUDIES HAVE PROGRESSIVELY PROVIDED A BETTER KNOWLEDGE OF THE UNDERLYING MECHANISMS BY WHICH AIR POLLUTION-DERIVED PARTICULATE MATTER (PM) EXERTS ITS HARMFUL HEALTH EFFECTS, FURTHER IN VITRO STUDIES ON RELEVANT CELL SYSTEMS ARE STILL NEEDED. HENCE, AIMING OF GETTING CLOSER TO THE HUMAN IN VIVO CONDITIONS, PRIMARY HUMAN BRONCHIAL EPITHELIAL CELLS DERIVED FROM NORMAL SUBJECTS (NHBE) OR SENSITIVE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD)-DISEASED PATIENTS (DHBE) WERE DIFFERENTIATED AT THE AIR-LIQUID INTERFACE. THEREAFTER, THEY WERE REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) TO STUDY THE OCCURRENCE OF SOME RELEVANT GENETIC AND/OR EPIGENETIC ENDPOINTS. CONCENTRATION-, EXPOSURE- AND SEASON-DEPENDENT INCREASES OF OH-B[A]P METABOLITES IN NHBE, AND TO A LESSER EXTENT, COPD-DHBE CELLS WERE REPORTED; HOWEVER, THERE WERE MORE TETRA-OH-B[A]P AND 8-OHDG DNA ADDUCTS IN COPD-DHBE CELLS. NO INCREASE IN PRIMARY DNA STRAND BREAK NOR CHROMOSOMAL ABERRATION WAS OBSERVED IN REPEATEDLY EXPOSED CELLS. TELOMERE LENGTH AND TELOMERASE ACTIVITY WERE MODIFIED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN NHBE AND PARTICULARLY COPD-DHBE CELLS. THERE WERE A GLOBAL DNA HYPOMETHYLATION, A P16 GENE PROMOTER HYPERMETHYLATION, AND A DECREASING DNA METHYLTRANSFERASE ACTIVITY IN NHBE AND NOTABLY COPD-DHBE CELLS REPEATEDLY EXPOSED. CHANGES IN SITE-SPECIFIC METHYLATION, ACETYLATION, AND PHOSPHORYLATION OF HISTONE H3 (I.E., H3K4ME3, H3K9AC, H3K27AC, AND H3S10PH) AND RELATED ENZYME ACTIVITIES OCCURRED IN A CONCENTRATION- AND EXPOSURE-DEPENDENT MANNER IN ALL THE REPEATEDLY EXPOSED CELLS. COLLECTIVELY, THESE RESULTS HIGHLIGHTED THE KEY ROLE PLAYED BY GENETIC AND EVEN EPIGENETIC EVENTS IN NHBE AND PARTICULARLY SENSITIVE COPD-DHBE CELLS REPEATEDLY EXPOSED TO AIR POLLUTION-DERIVED PM(2.5) AND THEIR DIFFERENT RESPONSIVENESS. WHILE THESE SPECIFIC EPIGENETIC CHANGES HAVE BEEN ALREADY DESCRIBED IN COPD AND EVEN LUNG CANCER PHENOTYPES, OUR FINDINGS SUPPORTED THAT, TOGETHER WITH GENETIC EVENTS, THESE EPIGENETIC EVENTS COULD DRAMATICALLY CONTRIBUTE TO THE SHIFT FROM HEALTHY TO DISEASED PHENOTYPES FOLLOWING REPEATED EXPOSURE TO RELATIVELY LOW DOSES OF AIR POLLUTION-DERIVED PM(2.5). 2017 15 4047 30 MAIN PATHOGENIC MECHANISMS AND RECENT ADVANCES IN COPD PERIPHERAL SKELETAL MUSCLE WASTING. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A WORLDWIDE PREVALENT RESPIRATORY DISEASE MAINLY CAUSED BY TOBACCO SMOKE EXPOSURE. COPD IS NOW CONSIDERED AS A SYSTEMIC DISEASE WITH SEVERAL COMORBIDITIES. AMONG THEM, SKELETAL MUSCLE DYSFUNCTION AFFECTS AROUND 20% OF COPD PATIENTS AND IS ASSOCIATED WITH HIGHER MORBIDITY AND MORTALITY. ALTHOUGH THE HISTOLOGICAL ALTERATIONS ARE WELL CHARACTERIZED, INCLUDING MYOFIBER ATROPHY, A DECREASED PROPORTION OF SLOW-TWITCH MYOFIBERS, AND A DECREASED CAPILLARIZATION AND OXIDATIVE PHOSPHORYLATION CAPACITY, THE MOLECULAR BASIS FOR MUSCLE ATROPHY IS COMPLEX AND REMAINS PARTLY UNKNOWN. MAJOR DIFFICULTIES LIE IN PATIENT HETEROGENEITY, ACCESSING PATIENTS' SAMPLES, AND COMPLEX MULTIFACTORIAL PROCESS INCLUDING EXTRINSIC MECHANISMS, SUCH AS TOBACCO SMOKE OR DISUSE, AND INTRINSIC MECHANISMS, SUCH AS OXIDATIVE STRESS, HYPOXIA, OR SYSTEMIC INFLAMMATION. MUSCLE WASTING IS ALSO A HIGHLY DYNAMIC PROCESS WHOSE INVESTIGATION IS HAMPERED BY THE DIFFERENTIAL PROTEIN REGULATION ACCORDING TO THE STAGE OF ATROPHY. IN THIS REVIEW, WE REPORT AND DISCUSS RECENT DATA REGARDING THE MOLECULAR ALTERATIONS IN COPD LEADING TO IMPAIRED MUSCLE MASS, INCLUDING INFLAMMATION, HYPOXIA AND HYPERCAPNIA, MITOCHONDRIAL DYSFUNCTION, DIVERSE METABOLIC CHANGES SUCH AS OXIDATIVE AND NITROSATIVE STRESS AND GENETIC AND EPIGENETIC MODIFICATIONS, ALL LEADING TO AN IMPAIRED ANABOLIC/CATABOLIC BALANCE IN THE MYOCYTE. WE RECAPITULATE DATA CONCERNING SKELETAL MUSCLE DYSFUNCTION OBTAINED IN THE DIFFERENT RODENT MODELS OF COPD. FINALLY, WE PROPOSE SEVERAL PATHWAYS THAT SHOULD BE INVESTIGATED IN COPD SKELETAL MUSCLE DYSFUNCTION IN THE FUTURE. 2023 16 4544 34 MUSCLE HYPERTROPHY IN HYPOXIA WITH INFLAMMATION IS CONTROLLED BY BROMODOMAIN AND EXTRA-TERMINAL DOMAIN PROTEINS. SOME OF THE CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) PATIENTS ENGAGED IN EXERCISE-BASED MUSCLE REHABILITATION PROGRAMS ARE UNRESPONSIVE. TO UNRAVEL THE RESPECTIVE ROLE OF CHRONIC HYPOXIA AND PULMONARY INFLAMMATION ON SOLEUS MUSCLE HYPERTROPHIC CAPACITIES, WE CHALLENGED MALE WISTAR RATS TO REPEATED LIPOPOLYSACCHARIDE INSTILLATIONS, ASSOCIATED OR NOT WITH A CHRONIC HYPOXIA EXPOSURE. MUSCLE HYPERTROPHY WAS INITIATED BY BILATERAL ABLATION OF SOLEUS AGONISTS 1 WEEK BEFORE SACRIFICE. TO UNDERSTAND THE ROLE PLAYED BY THE HISTONE ACETYLATION, WE ALSO TREATED OUR ANIMALS WITH AN INHIBITOR OF BROMODOMAINS AND EXTRA TERMINAL PROTEINS (I-BET) DURING THE WEEK AFTER SURGERY. PULMONARY INFLAMMATION TOTALLY INHIBITED THIS HYPERTROPHY RESPONSE UNDER BOTH NORMOXIC AND HYPOXIC CONDITIONS (26% LOWER THAN CONTROL SURGERY, P < 0.05), CONSISTENT WITH THE S6K1 AND MYOGENIN MEASUREMENTS. CHANGES IN HISTONE ACETYLATION AND CLASS IIA HISTONE DEACETYLASES EXPRESSION, FOLLOWING PULMONARY INFLAMMATION, SUGGESTED A PUTATIVE ROLE FOR HISTONE ACETYLATION SIGNALING IN THE ALTERED HYPERTROPHY RESPONSE. THE I-BET DRUG RESTORED THE HYPERTROPHY RESPONSE SUGGESTING THAT THE NON-RESPONSE OF MUSCLE TO A HYPERTROPHIC STIMULUS COULD BE MODULATED BY EPIGENETIC MECHANISMS, INCLUDING HISTONE-ACETYLATION DEPENDANT PATHWAYS. DRUGS TARGETING SUCH EPIGENETIC MECHANISMS MAY OPEN THERAPEUTIC PERSPECTIVES FOR COPD PATIENTS WITH SYSTEMIC INFLAMMATION WHO ARE UNRESPONSIVE TO REHABILITATION. 2017 17 2681 25 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 18 2348 35 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 19 3722 32 INHIBITION OF DNA METHYLATION DURING CHRONIC OBSTRUCTIVE BLADDER DISEASE (COBD) IMPROVES FUNCTION, PATHOLOGY AND EXPRESSION. PARTIAL BLADDER OUTLET OBSTRUCTION DUE TO PROSTATE HYPERPLASIA OR POSTERIOR URETHRAL VALVES, IS A WIDESPREAD CAUSE OF URINARY DYSFUNCTION, PATIENT DISCOMFORT AND ALSO RESPONSIBLE FOR IMMENSE HEALTH CARE COSTS. EVEN AFTER REMOVAL OR RELIEF OF OBSTRUCTION, THE FUNCTIONAL AND PATHOLOGIC ASPECTS OF OBSTRUCTION REMAIN AS A CHRONIC OBSTRUCTIVE BLADDER DISEASE (COBD). EPIGENETIC CHANGES, SUCH AS DNA METHYLATION, CONTRIBUTE TO THE PERSISTENT CHARACTER OF MANY CHRONIC DISEASES, AND MAY BE ALTERED IN COBD. WE TESTED WHETHER CANDIDATE GENES AND PATHWAYS AND THE PATHOPHYSIOLOGY OF COBD WERE AFFECTED BY A HYPOMETHYLATING AGENT, DECITABINE (DAC). COBD WAS CREATED IN FEMALE SPRAGUE-DAWLEY RATS BY SURGICAL LIGATION OF THE URETHRA FOR 6 WEEKS, FOLLOWED BY REMOVAL OF THE SUTURE. SHAM LIGATIONS WERE PERFORMED BY PASSING THE SUTURE BEHIND THE URETHRA. AFTER REMOVAL OF THE OBSTRUCTION OR SHAM REMOVAL, ANIMALS WERE RANDOMIZED TO DAC TREATMENT (1 MG/KG/3-TIMES/WEEK INTRAPERITONEALLY) OR VEHICLE (NORMAL SALINE). BLADDER FUNCTION WAS NON-INVASIVELY TESTED USING METABOLIC CAGES, BOTH ONE DAY PRIOR TO DE-OBSTRUCTION AT 6 WEEKS AND PRIOR TO SACRIFICE AT 10 WEEKS. RESIDUAL VOLUME AND BLADDER MASS WERE MEASURED FOR EACH BLADDER. BLADDERS WERE EXAMINED BY IMMUNOSTAINING AS WELL AS QPCR. THE EFFECTS OF DNA METHYLTRANSFERASE (DNMT)-3A KNOCKOUT OR OVEREXPRESSION ON SMOOTH MUSCLE CELL (SMC) FUNCTION AND PHENOTYPE WERE ALSO EXAMINED IN BLADDER SMC AND EX VIVO CULTURE. RESIDUAL VOLUMES OF THE DAC TREATED GROUP WERE NOT SIGNIFICANTLY DIFFERENT FROM THE NS GROUP. COMPARED TO COBD NS, COBD DAC TREATMENT HELPED PRESERVE MICTURITION VOLUME WITH A SIGNIFICANT RECOVERY OF THE VOIDING EFFICIENCY (RATIO OF THE MAXIMUM VOIDED VOLUME/MAXIMUM BLADDER CAPACITY) BY ONE THIRD (FIG. 1, P > 0.05). BRAIN-DERIVED NEUROTROPHIC FACTOR (BDNF) VARIANTS 1 AND 5 WERE UPREGULATED BY COBD AND SIGNIFICANTLY REDUCED BY DAC TREATMENT. DEPOSITION OF COLLAGEN IN THE COBD BLADDER WAS REDUCED BY DAC, BUT GROSS HYPERTROPHY REMAINED. IN BLADDER SMC, DNMT3A OVEREXPRESSION LED TO A LOSS OF CONTRACTILE FUNCTION AND PHENOTYPE. IN BLADDERS, PERSISTENTLY ALTERED BY COBD, INHIBITION OF DNA-METHYLATION ENHANCES FUNCTIONAL RECOVERY, UNLIKE TREATMENT DURING PARTIAL OBSTRUCTION, WHICH EXACERBATES OBSTRUCTIVE PATHOLOGY. THE UNDERLYING MECHANISMS MAY RELATE TO THE GENE EXPRESSION CHANGES IN BDNF AND THEIR EFFECTS ON SIGNALING IN THE BLADDER. 2021 20 3767 27 INTEGRATIVE EPIGENOMIC ANALYSIS IN DIFFERENTIATED HUMAN PRIMARY BRONCHIAL EPITHELIAL CELLS EXPOSED TO CIGARETTE SMOKE. CIGARETTE SMOKE (CS) IS ONE OF THE MAJOR RISK FACTORS FOR MANY PULMONARY DISEASES, INCLUDING CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) AND LUNG CANCER. THE FIRST LINE OF DEFENSE FOR CS EXPOSURE IS THE BRONCHIAL EPITHELIAL CELLS. ELUCIDATION OF THE EPIGENETIC CHANGES DURING CS EXPOSURE IS KEY TO GAINING A MECHANISTIC UNDERSTANDING INTO HOW MATURE AND DIFFERENTIATED BRONCHIAL EPITHELIAL CELLS RESPOND TO CS. THEREFORE, WE PERFORMED EPIGENOMIC PROFILING IN CONJUNCTION WITH TRANSCRIPTIONAL PROFILING IN WELL-DIFFERENTIATED HUMAN BRONCHIAL EPITHELIAL (HBE) CELLS CULTURED IN AIR-LIQUID INTERFACE (ALI) EXPOSED TO THE VAPOR PHASE OF CS. THE GENOME-WIDE ENRICHMENT OF HISTONE 3 LYSINE 27 ACETYLATION WAS DETECTED BY CHROMATIN IMMUNOPRECIPITATION FOLLOWED BY NEXT GENERATION SEQUENCING (CHIP-SEQ) IN HBE CELLS AND SUGGESTED THE PLAUSIBLE BINDING OF SPECIFIC TRANSCRIPTION FACTORS RELATED TO CS EXPOSURE. ADDITIONALLY, INTERROGATION OF CHIP-SEQ DATA WITH GENE EXPRESSION PROFILING OF HBE CELLS AFTER CS EXPOSURE FOR DIFFERENT DURATIONS (3 HOURS, 2 DAYS, 4 DAYS) SUGGESTED THAT EARLIER EPIGENETIC CHANGES (3 HOURS AFTER CS EXPOSURE) MAY BE ASSOCIATED WITH LATER GENE EXPRESSION CHANGES INDUCED BY CS EXPOSURE (4 DAYS). THE INTEGRATION OF EPIGENETICS AND GENE EXPRESSION DATA REVEALED SIGNALING PATHWAYS RELATED TO CS-INDUCED EPIGENETIC CHANGES IN HBE CELLS THAT MAY IDENTIFY NOVEL REGULATORY PATHWAYS RELATED TO CS-INDUCED COPD. 2018