1 1633 146 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 2 4543 49 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 3 4410 45 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 4 2385 37 EPIGENETIC REGULATORS OF THE REVASCULARIZATION RESPONSE TO CHRONIC ARTERIAL OCCLUSION. PERIPHERAL ARTERIAL DISEASE (PAD) IS THE LEADING CAUSE OF LOWER LIMB AMPUTATION AND ESTIMATED TO AFFECT OVER 202 MILLION PEOPLE WORLDWIDE. PAD IS CAUSED BY ATHEROSCLEROTIC LESIONS THAT OCCLUDE LARGE ARTERIES IN THE LOWER LIMBS, LEADING TO INSUFFICIENT BLOOD PERFUSION OF DISTAL TISSUES. GIVEN THE SEVERITY OF THIS CLINICAL PROBLEM, THERE HAS BEEN LONG-STANDING INTEREST IN BOTH UNDERSTANDING HOW CHRONIC ARTERIAL OCCLUSIONS AFFECT MUSCLE TISSUE AND VASCULATURE AND IDENTIFYING THERAPEUTIC APPROACHES CAPABLE OF RESTORING TISSUE COMPOSITION AND VASCULAR FUNCTION TO A HEALTHY STATE. TO DATE, THE MOST WIDELY UTILIZED ANIMAL MODEL FOR PERFORMING SUCH STUDIES HAS BEEN THE ISCHAEMIC MOUSE HINDLIMB. DESPITE NOT BEING A MODEL OF PAD PER SE, THE ISCHAEMIC HINDLIMB MODEL DOES RECAPITULATE SEVERAL KEY ASPECTS OF PAD. FURTHER, IT HAS SERVED AS A VALUABLE PLATFORM UPON WHICH WE HAVE BUILT MUCH OF OUR UNDERSTANDING OF HOW CHRONIC ARTERIAL OCCLUSIONS AFFECT MUSCLE TISSUE COMPOSITION, MUSCLE REGENERATION AND ANGIOGENESIS, AND COLLATERAL ARTERIOGENESIS. RECENTLY, THERE HAS BEEN A GLOBAL SURGE IN RESEARCH AIMED AT UNDERSTANDING HOW GENE EXPRESSION IS REGULATED BY EPIGENETIC FACTORS (I.E. NON-CODING RNAS, HISTONE POST-TRANSLATIONAL MODIFICATIONS, AND DNA METHYLATION). THUS, PERHAPS NOT UNEXPECTEDLY, MANY RECENT STUDIES HAVE IDENTIFIED ESSENTIAL ROLES FOR EPIGENETIC FACTORS IN REGULATING KEY RESPONSES TO CHRONIC ARTERIAL OCCLUSION(S). IN THIS REVIEW, WE SUMMARIZE THE MECHANISMS OF ACTION OF THESE EPIGENETIC REGULATORS AND HIGHLIGHT SEVERAL RECENT STUDIES INVESTIGATING THE ROLE OF SAID REGULATORS IN THE CONTEXT OF HINDLIMB ISCHAEMIA. IN ADDITION, WE FOCUS ON HOW THESE RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF EPIGENETICS IN REGULATING RESPONSES TO CHRONIC ARTERIAL OCCLUSION(S) CAN INFORM FUTURE THERAPEUTIC APPLICATIONS TO PROMOTE REVASCULARIZATION AND PERFUSION RECOVERY IN THE SETTING OF PAD. 2019 5 5334 71 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 6 2505 59 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 7 2953 26 GENETIC AND EPIGENETIC EVENTS IN DIABETIC WOUND HEALING. THE PREVALENCE OF THE CHRONIC METABOLIC DISORDER, DIABETES MELLITUS, IS EXPECTED TO INCREASE IN THE COMING YEARS AND WORLDWIDE PANDEMIC LEVELS ARE PREDICTED. INEVITABLY, THIS WILL BE ACCOMPANIED BY AN INCREASE IN THE PREVALENCE OF DIABETIC COMPLICATIONS, INCLUDING DIABETIC FOOT ULCERS. AT PRESENT, TREATMENT OPTIONS FOR DIABETIC FOOT ULCERS ARE IN MANY CASES INSUFFICIENT, AND PROGRESSION OF THE CONDITION RESULTS IN THE REQUIREMENT FOR LIMB AMPUTATION IN A PROPORTION OF PATIENTS. TO IMPROVE THERAPY, AN INCREASE IN OUR UNDERSTANDING OF THE PATHOBIOLOGY OF DIABETIC COMPLICATIONS SUCH AS IMPAIRED WOUND HEALING IS NECESSARY. IN THIS REVIEW, RECENT ADVANCES IN MOLECULAR ASPECTS OF NORMAL AND IMPAIRED DIABETIC WOUND HEALING ARE DISCUSSED. FURTHERMORE, INVESTIGATIONS OF THE ROLE OF EPIGENETIC PROCESSES IN THE PATHOGENESIS OF IMPAIRED DIABETIC WOUND HEALING ARE NOW EMERGING. INDEED, EPIGENETIC CHANGES HAVE ALREADY BEEN IDENTIFIED AS KEY FACTORS IN DIABETES AND RELATED COMPLICATIONS AND THESE ARE OVERVIEWED IN THIS REVIEW. 2011 8 5922 30 TARGETING DNA METHYLATION AND DEMETHYLATION IN DIABETIC FOOT ULCERS. BACKGROUND: POOR WOUND HEALING IS A SIGNIFICANT COMPLICATION OF DIABETES, WHICH IS COMMONLY CAUSED BY NEUROPATHY, TRAUMA, DEFORMITIES, PLANTAR HYPERTENSION AND PERIPHERAL ARTERIAL DISEASE. DIABETIC FOOT ULCERS (DFU) ARE DIFFICULT TO HEAL, WHICH MAKES PATIENTS SUSCEPTIBLE TO INFECTIONS AND CAN ULTIMATELY CONDUCE TO LIMB AMPUTATION OR EVEN DEATH IN SEVERE CASES. AN INCREASING NUMBER OF STUDIES HAVE FOUND THAT EPIGENETIC ALTERATIONS ARE STRONGLY ASSOCIATED WITH POOR WOUND HEALING IN DIABETES. AIM OF REVIEW: THIS WORK PROVIDES SIGNIFICANT INSIGHTS INTO THE DEVELOPMENT OF THERAPEUTICS FOR IMPROVING CHRONIC DIABETIC WOUND HEALING, PARTICULARLY BY TARGETING AND REGULATING DNA METHYLATION AND DEMETHYLATION IN DFU. KEY SCIENTIFIC CONCEPTS OF REVIEW: DNA METHYLATION AND DEMETHYLATION PLAY AN IMPORTANT PART IN DIABETIC WOUND HEALING, VIA REGULATING CORRESPONDING SIGNALING PATHWAYS IN DIFFERENT BREEDS OF CELLS, INCLUDING MACROPHAGES, VASCULAR ENDOTHELIAL CELLS AND KERATINOCYTES. IN THIS REVIEW, WE DESCRIBE THE FOUR MAIN PHASES OF WOUND HEALING AND THEIR ABNORMALITY IN DIABETIC PATIENTS. FURTHERMORE, WE PROVIDED AN IN-DEPTH SUMMARY AND DISCUSSION ON HOW DNA METHYLATION AND DEMETHYLATION REGULATE DIABETIC WOUND HEALING IN DIFFERENT TYPES OF CELLS; AND GAVE A BRIEF SUMMARY ON RECENT ADVANCES IN APPLYING CELLULAR REPROGRAMMING TECHNIQUES FOR IMPROVING DIABETIC WOUND HEALING. 2023 9 4047 42 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 10 4577 37 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 11 2976 32 GENETIC AND MOLECULAR BASIS OF DIABETIC FOOT ULCERS: CLINICAL REVIEW. DIABETIC FOOT ULCERS (DFUS) ARE MAJOR COMPLICATIONS ASSOCIATED WITH DIABETES AND OFTEN CORRELATE WITH PERIPHERAL NEUROPATHY, TRAUMA AND PERIPHERAL VASCULAR DISEASE. IT IS NECESSARY TO UNDERSTAND THE MOLECULAR AND GENETIC BASIS OF DIABETIC FOOT ULCERS IN ORDER TO TAILOR PATIENT CENTRED CARE TOWARDS PARTICULAR PATIENT GROUPS. THIS REVIEW AIMED TO EVALUATE WHETHER CURRENT LITERATURE WAS INDICATIVE OF AN UNDERLYING MOLECULAR AND GENETIC BASIS FOR DFUS AND TO DISCUSS CLINICAL APPLICATIONS. FROM A MOLECULAR PERSPECTIVE, WOUND HEALING IS A PROCESS THAT TRANSPIRES FOLLOWING BREACH OF THE SKIN BARRIER AND IS USUALLY MEDIATED BY GROWTH FACTORS AND CYTOKINES RELEASED BY SPECIALISED CELLS ACTIVATED BY THE IMMUNE RESPONSE, INCLUDING FIBROBLASTS, ENDOTHELIAL CELLS, PHAGOCYTES, PLATELETS AND KERATINOCYTES. GROWTH FACTORS AND CYTOKINES ARE FUNDAMENTAL IN THE ORGANISATION OF THE MOLECULAR PROCESSES INVOLVED IN MAKING CUTANEOUS WOUND HEALING POSSIBLE. THERE IS A SIGNIFICANT ROLE FOR SINGLE NUCLEOTIDE POLYMORPHISM (SNPS) IN THE FLUCTUATION OF THESE GROWTH FACTORS AND CYTOKINES IN DFUS. FURTHERMORE, RECENT EVIDENCE SUGGESTS A KEY ROLE FOR EPIGENETIC MECHANISMS SUCH AS DNA METHYLATION FROM LONG STANDING HYPERGLYCEMIA AND NON-CODING RNAS IN THE COMPLEX INTERPLAY BETWEEN GENES AND THE ENVIRONMENT. GENETIC FACTORS AND ETHNICITY CAN ALSO PLAY A SIGNIFICANT ROLE IN THE DEVELOPMENT OF DIABETIC NEUROPATHY LEADING TO DFUS. CLINICALLY, INTERVENTIONS WHICH HAVE IMPROVED OUTCOMES FOR PEOPLE WITH DFUS OR THOSE AT RISK OF DFUS INCLUDE SOME SYSTEMIC THERAPEUTIC DRUG INTERVENTIONS WHICH IMPROVE MICROVASCULAR BLOOD FLOW, SURGICAL INTERVENTIONS, HUMAN GROWTH FACTORS, AND HYPERBARIC OXYGEN THERAPY, NEGATIVE PRESSURE WOUND THERAPY, SKIN REPLACEMENT OR SHOCKWAVE THERAPY AND THE USE OF TOPICAL TREATMENTS. FUTURE TREATMENT MODALITIES INCLUDING STEM CELL AND GENE THERAPIES ARE PROMISING IN THE THERAPEUTIC APPROACH TO PREVENT THE PROGRESSION OF CHRONIC DIABETIC COMPLICATIONS. 2016 12 1713 28 DYSFUNCTIONAL WOUND HEALING IN DIABETIC FOOT ULCERS: NEW CROSSROADS. PURPOSE OF REVIEW: DIABETIC FOOT ULCERATIONS (DFU) AFFECT 25% OF PATIENTS WITH DIABETES MELLITUS DURING THEIR LIFETIME AND CONSTITUTE A MAJOR HEALTH PROBLEM AS THEY ARE OFTEN RECALCITRANT TO HEALING DUE TO A CONSTELLATION OF BOTH INTRINSIC AND EXTRINSIC FACTORS. THE PURPOSE OF THIS REVIEW IS TO (1) DETAIL THE CURRENT MECHANISTIC UNDERSTANDING OF DFU FORMATION AND (2) HIGHLIGHT FUTURE THERAPEUTIC TARGETS. RECENT FINDINGS: FROM A MOLECULAR PERSPECTIVE, DFUS EXHIBIT A CHRONIC INFLAMMATORY PREDISPOSITION. IN ADDITION, INCREASED LOCAL HYPOXIC CONDITIONS AND IMPAIRED CELLULAR RESPONSES TO HYPOXIA ARE PATHOGENIC FACTORS THAT CONTRIBUTE TO DELAYED WOUND HEALING. FINALLY, RECENT EVIDENCE SUGGESTS A ROLE FOR EPIGENETIC ALTERATIONS, INCLUDING MICRORNAS, IN DELAYED DFU HEALING DUE TO THE COMPLEX INTERPLAY BETWEEN GENES AND THE ENVIRONMENT. IN THIS REGARD, NOTABLE PROGRESS HAS BEEN MADE IN THE MOLECULAR AND GENETIC UNDERSTANDING OF DFU FORMATION. HOWEVER, FURTHER STUDIES ARE NEEDED TO TRANSLATE PRECLINICAL INVESTIGATIONS INTO CLINICAL THERAPIES. 2018 13 5679 41 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 14 246 29 ADULT STEM CELL THERAPY FOR CARDIAC REPAIR IN PATIENTS AFTER ACUTE MYOCARDIAL INFARCTION LEADING TO ISCHEMIC HEART FAILURE: AN OVERVIEW OF EVIDENCE FROM THE RECENT CLINICAL TRIALS. BACKGROUND: CARDIOVASCULAR DISEASES (CVD) STILL REPRESENT THE LEADING CAUSE OF MORTALITY WORLDWIDE, DESPITE THE REMARKABLE ADVANCES IN INTERVENTIONAL CARDIOLOGY, CARDIAC SURGERY, AND MODERN PHARMACOTHERAPY, PARTICULARLY IN THE SETTING OF ACUTE MYOCARDIAL INFARCTION (AMI), CHRONIC ISCHEMIC HEART FAILURE (HF), CARDIOMYOPATHY (CM), AND THE ASSOCIATED LEFT VENTRICULAR (LV) DYSFUNCTION. A SIGNIFICANT LOSS OF CARDIOMYOCYTES THAT UNDERLIES ALL OF THESE CONDITIONS WAS PREVIOUSLY CONSIDERED IRREVERSIBLE. HOWEVER, CURRENT EVIDENCE INDICATES THAT THE HUMAN HEART HAS SOME POTENTIAL FOR REPAIR, AND OVER THE PAST DECADE, MANY RESEARCH STUDIES HAVE BEEN EXPLORING THE USE OF STEM CELLS (SCS) TO FACILITATE RESTORATION OF MYOCARDIUM. CONSEQUENTLY, THE SAFETY, FEASIBILITY, AND EFFECTIVENESS OF SC THERAPY HAVE BEEN REPORTED IN MANY RANDOMIZED CLINICAL TRIALS (RCTS), USING DIFFERENT LINEAGES OF ADULT SCS. NEVERTHELESS, THE CLINICAL BENEFITS OF SC THERAPY ARE NOT YET WELL ESTABLISHED. IN THE NEAR FUTURE, UNDERSTANDING OF THE COMPLEX INTERRELATIONS BETWEEN SCS, PARACRINE FACTORS, GENETIC OR EPIGENETIC PREDISPOSITIONS, AND MYOCARDIAL MICROENVIRONMENT, IN THE CONTEXT OF AN INDIVIDUAL PATIENT, WILL BE CRUCIAL FOR TRANSLATION OF THIS KNOWLEDGE INTO PRACTICAL DEVELOPMENT OF SUCCESSFUL, LONG-TERM REGENERATIVE SC THERAPEUTIC APPLICATIONS, IN A GROWING POPULATION OF PATIENTS SUFFERING FROM PREVIOUS MYOCARDIAL INFARCTION (MI) LEADING TO CHRONIC ISCHEMIC CARDIOMYOPATHY. CONCLUSION: THIS OVERVIEW HIGHLIGHTS THE THERAPEUTIC POTENTIAL OF ADULT SCS IN TERMS OF THEIR POSSIBLE REGENERATIVE CAPACITY, SAFETY, AND CLINICAL OUTCOMES, IN PATIENTS WITH AMI, AND/OR SUBSEQUENT HF (DUE TO CHRONIC ISCHEMIC CARDIOMYOPATHY). THIS REVIEW WAS BASED UPON PUBMED DATABASE SEARCH FOR TRIALS ON SC THERAPY, IN PATIENTS WITH AMI AND HF, AND THE MAIN TIMEFRAME WAS SET FROM 2006 TO 2016. 2017 15 1886 29 ENDOGENOUS BIOLOGICAL DRIVERS IN DIABETIC LOWER LIMB WOUNDS RECURRENCE: HYPOTHETICAL REFLECTIONS. AN IMPAIRED HEALING RESPONSE UNDERLIES DIABETIC FOOT WOUND CHRONICITY, FREQUENTLY TRANSLATING TO AMPUTATION, DISABILITY, AND MORTALITY. DIABETICS SUFFER FROM UNDERAPPRECIATED EPISODES OF POST-EPITHELIZATION ULCER RECURRENCE. RECURRENCE EPIDEMIOLOGICAL DATA ARE ALARMINGLY HIGH, SO THE ULCER IS CONSIDERED IN "REMISSION" AND NOT HEALED FROM THE TIME IT REMAINS EPITHELIALIZED. RECURRENCE MAY RESULT FROM THE COMBINED EFFECTS OF BEHAVIORAL AND ENDOGENOUS BIOLOGICAL FACTORS. ALTHOUGH THE DAMAGING ROLE OF BEHAVIORAL, CLINICAL PREDISPOSING FACTORS IS UNDEBATABLE, IT STILL REMAINS ELUSIVE IN THE IDENTIFICATION OF ENDOGENOUS BIOLOGICAL CULPRITS THAT MAY PRIME THE RESIDUAL SCAR TISSUE FOR RECURRENCE. FURTHERMORE, THE EVENT OF ULCER RECURRENCE STILL WAITS FOR THE IDENTIFICATION OF A MOLECULAR PREDICTOR. WE PROPOSE THAT ULCER RECURRENCE IS DEEPLY IMPINGED BY CHRONIC HYPERGLYCEMIA AND ITS DOWNSTREAM BIOLOGICAL EFFECTORS, WHICH ORIGINATE EPIGENETIC DRIVERS THAT ENFORCE ABNORMAL PATHOLOGIC PHENOTYPES TO DERMAL FIBROBLASTS AND KERATINOCYTES AS MEMORY CELLS. HYPERGLYCEMIA-DERIVED CYTOTOXIC REACTANTS ACCUMULATE AND MODIFY DERMAL PROTEINS, REDUCE SCAR TISSUE MECHANICAL TOLERANCE, AND DISRUPT FIBROBLAST-SECRETORY ACTIVITY. ACCORDINGLY, THE COMBINATION OF EPIGENETIC AND LOCAL AND SYSTEMIC CYTOTOXIC SIGNALERS INDUCE THE ONSET OF "AT-RISK PHENOTYPES" SUCH AS PREMATURE SKIN CELL AGING, DYSMETABOLISM, INFLAMMATORY, PRO-DEGRADATIVE, AND OXIDATIVE PROGRAMS THAT MAY ULTIMATELY CONVERGE TO SCAR CELL DEMISE. POST-EPITHELIALIZATION RECURRENCE RATE DATA ARE MISSING IN CLINICAL STUDIES OF REPUTED ULCER HEALING THERAPIES DURING FOLLOW-UP PERIODS. INTRA-ULCER INFILTRATION OF EPIDERMAL GROWTH FACTOR EXHIBITS THE MOST CONSISTENT REMISSION DATA WITH THE LOWEST RECURRENCES DURING 12-MONTH FOLLOW-UP. RECURRENCE DATA SHOULD BE REGARDED AS A VALUABLE CLINICAL ENDPOINT DURING THE INVESTIGATIONAL PERIOD FOR EACH EMERGENT HEALING CANDIDATE. 2023 16 2170 77 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 17 465 34 ARE TARGETED THERAPIES FOR DIABETIC CARDIOMYOPATHY ON THE HORIZON? DIABETES INCREASES THE RISK OF HEART FAILURE APPROXIMATELY 2.5-FOLD, INDEPENDENT OF CORONARY ARTERY DISEASE AND OTHER COMORBIDITIES. THIS PROCESS, TERMED DIABETIC CARDIOMYOPATHY, IS CHARACTERIZED BY INITIAL IMPAIRMENT OF LEFT VENTRICULAR (LV) RELAXATION FOLLOWED BY LV CONTRACTILE DYSFUNCTION. POST-MORTEM EXAMINATION REVEALS THAT HUMAN DIASTOLIC DYSFUNCTION IS CLOSELY ASSOCIATED WITH LV DAMAGE, INCLUDING CARDIOMYOCYTE HYPERTROPHY, APOPTOSIS AND FIBROSIS, WITH IMPAIRED CORONARY MICROVASCULAR PERFUSION. THE PATHOPHYSIOLOGICAL MECHANISMS UNDERPINNING THE CHARACTERISTIC FEATURES OF DIABETIC CARDIOMYOPATHY REMAIN POORLY UNDERSTOOD, ALTHOUGH MULTIPLE FACTORS INCLUDING ALTERED LIPID METABOLISM, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, ENDOPLASMIC RETICULUM (ER) STRESS, INFLAMMATION, AS WELL AS EPIGENETIC CHANGES, ARE IMPLICATED. DESPITE A RECENT RISE IN RESEARCH INTERROGATING THESE MECHANISMS AND AN INCREASED UNDERSTANDING OF THE CLINICAL IMPORTANCE OF DIABETIC CARDIOMYOPATHY, THERE REMAINS A LACK OF SPECIFIC TREATMENT STRATEGIES. HOW THE CHRONIC METABOLIC DISTURBANCES OBSERVED IN DIABETES LEAD TO STRUCTURAL AND FUNCTIONAL CHANGES REMAINS A PERTINENT QUESTION, AND IT IS HOPED THAT RECENT ADVANCES, PARTICULARLY IN THE AREA OF EPIGENETICS, AMONG OTHERS, MAY PROVIDE SOME ANSWERS. THIS REVIEW HENCE EXPLORES THE TEMPORAL ONSET OF THE PATHOLOGICAL FEATURES OF DIABETIC CARDIOMYOPATHY, AND THEIR RELATIVE CONTRIBUTION TO THE RESULTANT DISEASE PHENOTYPE, AS WELL AS BOTH CURRENT AND POTENTIAL THERAPEUTIC OPTIONS. THE EMERGENCE OF GLUCOSE-OPTIMIZING AGENTS, NAMELY GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS AND SODIUM/GLUCOSE CO-TRANSPORTER (SGLT)2 INHIBITORS THAT CONFER BENEFITS ON CARDIOVASCULAR OUTCOMES, TOGETHER WITH NOVEL EXPERIMENTAL APPROACHES, HIGHLIGHT A NEW AND EXCITING ERA IN DIABETES RESEARCH, WHICH IS LIKELY TO RESULT IN MAJOR CLINICAL IMPACT. 2017 18 2171 25 EPIGENETIC MECHANISMS IN THE PATHOGENESIS OF DIABETIC FOOT ULCERS. THE INCIDENCE OF DIABETES MELLITUS, A CHRONIC METABOLIC DISEASE ASSOCIATED WITH BOTH PREDISPOSING GENETIC AND ENVIRONMENTAL FACTORS, IS INCREASING GLOBALLY. AS A RESULT, IT IS EXPECTED THAT THERE WILL ALSO BE AN INCREASING INCIDENCE OF DIABETIC COMPLICATIONS WHICH ARISE AS A RESULT OF POOR GLYCEMIC CONTROL. COMPLICATIONS INCLUDE CARDIOVASCULAR DISEASES, NEPHROPATHY, RETINOPATHY AND DIABETIC FOOT ULCERS. THE FINDINGS OF SEVERAL MAJOR CLINICAL TRIALS HAVE IDENTIFIED THAT DIABETIC COMPLICATIONS MAY ARISE EVEN AFTER MANY YEARS OF PROPER GLYCEMIC CONTROL. THIS HAS LED TO THE CONCEPT OF PERSISTENT EPIGENETIC CHANGES. VARIOUS EPIGENETIC MECHANISMS HAVE BEEN IDENTIFIED AS IMPORTANT CONTRIBUTORS TO THE PATHOGENESIS OF DIABETES AND DIABETIC COMPLICATIONS. THE AIM OF THIS REVIEW IS TO PROVIDE AN OVERVIEW OF THE PATHOBIOLOGY OF TYPE 2 DIABETES WITH AN EMPHASIS ON COMPLICATIONS, PARTICULARLY DIABETIC FOOT ULCERS. AN OVERVIEW OF EPIGENETIC MECHANISMS IS PROVIDED AND THE FOCUS IS ON THE EMERGING EVIDENCE FOR ABERRANT EPIGENETIC MECHANISMS IN DIABETIC FOOT ULCERS. 2012 19 2348 50 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 20 5724 31 SKELETAL MUSCLE WASTING AND ITS RELATIONSHIP WITH OSTEOARTHRITIS: A MINI-REVIEW OF MECHANISMS AND CURRENT INTERVENTIONS. PURPOSE OF REVIEW: OSTEOARTHRITIS (OA) IS A SUBSET OF JOINT DISORDERS RESULTING IN DEGENERATION OF SYNOVIAL JOINTS. THIS LEADS TO PAIN, DISABILITY AND LOSS OF INDEPENDENCE. KNEE AND HIP OA ARE EXTREMELY PREVALENT, AND THEIR OCCURRENCE INCREASES WITH AGEING. SIMILARLY, LOSS OF MUSCLE MASS AND FUNCTION, SARCOPENIA, OCCURS DURING AGEING. RECENT FINDINGS: LITTLE IS KNOWN ABOUT THE IMPACT OF MUSCLE WASTING ON OA PROGRESSION; NEVERTHELESS, IT HAS BEEN SUGGESTED THAT MUSCLE WASTING DIRECTLY AFFECTS THE STABILITY OF THE JOINTS AND LOSS OF MOBILITY LEADS TO GRADUAL DEGENERATION OF ARTICULAR CARTILAGE. THE MOLECULAR MECHANISMS UNDERLYING MUSCLE WASTING IN OA ARE NOT WELL UNDERSTOOD; HOWEVER, THESE ARE PROBABLY RELATED TO CHANGES IN GENE EXPRESSION, AS WELL AS EPIGENETIC MODIFICATIONS. IT IS BECOMING CLEAR THAT SKELETAL MUSCLE WASTING PLAYS AN IMPORTANT ROLE IN OA DEVELOPMENT AND/OR PROGRESSION. HERE, WE DISCUSS MECHANISMS, CURRENT INTERVENTIONS, SUCH AS EXERCISE, AND POTENTIALLY NOVEL APPROACHES, SUCH AS MODULATION OF MICRORNAS, AIMING AT AMELIORATING OA SYMPTOMS THROUGH MAINTAINING MUSCLE MASS AND FUNCTION. 2019