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Mitochondria form a dynamic network within skeletal muscle. This network is not only responsible for producing adenine triphosphate through oxidative phosphorylation, but also responds through fission, fusion and mitophagy to various factors, such as increased energy demands, oxidative stress, inflammation, and calcium dysregulation. Mitochondrial dysfunction in skeletal muscle not only occurs in primary mitochondrial myopathies, but also other hereditary and acquired myopathies. As such, this review attempts to highlight the clinical and histopathologic aspects of mitochondrial dysfunction seen in hereditary and acquired myopathies, as well as discuss potential mechanisms leading to mitochondrial dysfunction and therapies to restore mitochondrial function.
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Glycosylphosphatidylinositols (GPIs) are a type of glycolipid responsible for anchoring many important proteins to the cell membrane surface. Defects in the synthesis of GPIs can lead to a group of multisystem disorders known as the inherited GPI deficiencies (IGDs). Homozygosity for the c.-270C > G variant in the promoter of PIGM has been associated with a IGD subtype known as glycosylphosphatidylinositol biosynthesis defect-1 (GPIBD1). The several cases reported in the literature have been described to have a milder neurologic phenotype in comparison to the other IGDs and have been treated with sodium phenylbutyrate with some degree of success. These patients typically present with portal and hepatic vein thrombosis and mostly develop absence seizures. Here we describe a patient homozygous for a nonsynonymous variant in PIGM who deceased at 9 weeks of life and had multiple physical dysmorphisms (rocker bottom feet, midline cleft palate, thickened and lichenified skin), portal vein thrombosis, CNS structural anomalies (progressive multicystic encephalomalacia and ventriculomegaly), and a neurological phenotype of a diffuse encephalopathy. This is the first known case report of a PIGM-related IGD/CDG due to a coding variant.
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Hereditary gelsolin amyloidosis is an adult onset autosomal dominant disease with neurologic, ophthalmologic and dermatologic features that may be mistaken for Sjögren syndrome. We describe a case of a 68 year old female presenting with facial numbness and asymmetry, dry eyes, dry mouth and fatigue, originally diagnosed as Sjögren syndrome and treated with hydroxychloroquine. Due to her insidious progression of facial weakness with associated proximal muscle weakness she underwent a muscle biopsy, which demonstrated features of hydroxychloroquine induced myopathy and amyloid deposition. This subsequently led to targeted genetic testing, revealing an autosomal dominant c.640G > A pathogenic variant of the gelsolin gene. Therefore, this is a unique case of complex muscle pathology with features of a rare hereditary systemic amyloidosis an uncommon drug- induced myopathy.
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Altered mitochondrial structure and function are implicated in the functional decline of skeletal muscle. Numerous cytoskeletal proteins are known to affect mitochondrial homeostasis, but this complex network is still being unraveled. Here, we investigated mitochondrial alterations in mice lacking the cytoskeletal adapter protein, XIN (XIN-/-). XIN-/- and wild-type littermate male and female mice were fed a chow or high-fat diet (HFD; 60% kcal fat) for 8 weeks before analyses of their skeletal muscles was conducted. Immuno-electron microscopy (EM) and immunofluorescence staining revealed XIN in the mitochondria and peri-mitochondrial areas, as well as the myoplasm. Intermyofibrillar mitochondria in chow-fed XIN-/- mice were notably different from wild-type (large, and/or swollen in appearance). Succinate Dehydrogenase and Cytochrome Oxidase IV staining indicated greater evidence of mitochondrial enzyme activity in XIN-/- mice. No difference in body mass gains or glucose handling was observed between cohorts with HFD. However, EM revealed significantly greater mitochondrial density with evident structural abnormalities (swelling, reduced cristae density) in XIN-/- mice. Absolute Complex I and II-supported respiration was not different between groups, but relative to mitochondrial density, was significantly lower in XIN-/-. These results provide the first evidence for a role of XIN in maintaining mitochondrial morphology and function.
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Short- and long-latency afferent inhibition (SAI and LAI respectively) are phenomenon whereby the motor evoked potential induced by transcranial magnetic stimulation (TMS) is inhibited by a sensory afferent volley consequent to nerve stimulation. It remains unclear whether dopamine participates in the genesis or modulation of SAI and LAI. The present study aimed to determine if SAI and LAI are modulated by levodopa (l-DOPA). In this placebo-controlled, double-anonymized study Apo-Levocarb (100 mg l-DOPA in combination with 25 mg carbidopa) and a placebo were administered to 32 adult males (mean age 24 ± 3 years) in two separate sessions. SAI and LAI were evoked by stimulating the median nerve and delivering single-pulse TMS over the motor hotspot corresponding to the first dorsal interosseous muscle of the right hand. SAI and LAI were quantified before and 1 h following ingestion of drug or placebo corresponding to the peak plasma concentration of Apo-Levocarb. The results indicate that Apo-Levocarb increases SAI and does not significantly alter LAI. These findings support literature demonstrating increased SAI following exogenous dopamine administration in neurodegenerative disorders. KEY POINTS: Short- and long-latency afferent inhibition (SAI and LAI respectively) are measures of corticospinal excitability evoked using transcranial magnetic stimulation. SAI and LAI are reduced in conditions such as Parkinson's disease which suggests dopamine may be involved in the mechanism of afferent inhibition. 125 mg of Apo-Levocarb (100 mg dopamine) increases SAI but not LAI. This study increases our understanding of the pharmacological mechanism of SAI and LAI.
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Carbidopa , Potenciales Evocados Motores , Levodopa , Estimulación Magnética Transcraneal , Humanos , Masculino , Levodopa/farmacología , Adulto , Potenciales Evocados Motores/efectos de los fármacos , Estimulación Magnética Transcraneal/métodos , Carbidopa/farmacología , Adulto Joven , Inhibición Neural/efectos de los fármacos , Método Doble Ciego , Dopaminérgicos/farmacología , Dopamina/farmacología , Combinación de Medicamentos , Nervio Mediano/fisiología , Nervio Mediano/efectos de los fármacosAsunto(s)
Complejo I de Transporte de Electrón , Heterocigoto , Secuenciación de Nucleótidos de Alto Rendimiento , Enfermedades Mitocondriales , Humanos , Complejo I de Transporte de Electrón/genética , Complejo I de Transporte de Electrón/deficiencia , Enfermedades Mitocondriales/genética , Enfermedades Mitocondriales/patología , Enfermedades Mitocondriales/diagnóstico , Eliminación de Secuencia/genética , Masculino , Femenino , NiñoRESUMEN
PURPOSE: To evaluate the diagnostic utility of publicly funded clinical exome sequencing (ES) for patients with suspected rare genetic diseases. METHODS: We prospectively enrolled 297 probands who met eligibility criteria and received ES across 5 sites in Ontario, Canada, and extracted data from medical records and clinician surveys. Using the Fryback and Thornbury Efficacy Framework, we assessed diagnostic accuracy by examining laboratory interpretation of results and assessed diagnostic thinking by examining the clinical interpretation of results and whether clinical-molecular diagnoses would have been achieved via alternative hypothetical molecular tests. RESULTS: Laboratories reported 105 molecular diagnoses and 165 uncertain results in known and novel genes. Of these, clinicians interpreted 102 of 105 (97%) molecular diagnoses and 6 of 165 (4%) uncertain results as clinical-molecular diagnoses. The 108 clinical-molecular diagnoses were in 104 families (35% diagnostic yield). Each eligibility criteria resulted in diagnostic yields of 30% to 40%, and higher yields were achieved when >2 eligibility criteria were met (up to 45%). Hypothetical tests would have identified 61% of clinical-molecular diagnoses. CONCLUSION: We demonstrate robustness in eligibility criteria and high clinical validity of laboratory results from ES testing. The importance of ES was highlighted by the potential 40% of patients that would have gone undiagnosed without this test.
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Exoma , Enfermedades Raras , Humanos , Estudios Prospectivos , Secuenciación del Exoma , Enfermedades Raras/diagnóstico , Enfermedades Raras/genética , Pruebas Genéticas/métodos , OntarioRESUMEN
Pre-mRNA splicing is a highly coordinated process. While its dysregulation has been linked to neurological deficits, our understanding of the underlying molecular and cellular mechanisms remains limited. We implicated pathogenic variants in U2AF2 and PRPF19, encoding spliceosome subunits in neurodevelopmental disorders (NDDs), by identifying 46 unrelated individuals with 23 de novo U2AF2 missense variants (including 7 recurrent variants in 30 individuals) and 6 individuals with de novo PRPF19 variants. Eight U2AF2 variants dysregulated splicing of a model substrate. Neuritogenesis was reduced in human neurons differentiated from human pluripotent stem cells carrying two U2AF2 hyper-recurrent variants. Neural loss of function (LoF) of the Drosophila orthologs U2af50 and Prp19 led to lethality, abnormal mushroom body (MB) patterning, and social deficits, which were differentially rescued by wild-type and mutant U2AF2 or PRPF19. Transcriptome profiling revealed splicing substrates or effectors (including Rbfox1, a third splicing factor), which rescued MB defects in U2af50-deficient flies. Upon reanalysis of negative clinical exomes followed by data sharing, we further identified 6 patients with NDD who carried RBFOX1 missense variants which, by in vitro testing, showed LoF. Our study implicates 3 splicing factors as NDD-causative genes and establishes a genetic network with hierarchy underlying human brain development and function.
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Trastornos del Neurodesarrollo , Empalmosomas , Humanos , Empalmosomas/genética , Redes Reguladoras de Genes , Trastornos del Neurodesarrollo/genética , Mutación Missense , Empalme del ARN , Factores de Empalme de ARN/genética , Proteínas Nucleares/genética , Enzimas Reparadoras del ADN/genéticaRESUMEN
Peripheral blood metabolomics was used to gain chemical insight into the biology of treatment-refractory Major Depressive Disorder with suicidal ideation, and to identify individualized differences for personalized care. The study cohort consisted of 99 patients with treatment-refractory major depressive disorder and suicidal ideation (trMDD-SI n = 52 females and 47 males) and 94 age- and sex-matched healthy controls (n = 48 females and 46 males). The median age was 29 years (IQR 22-42). Targeted, broad-spectrum metabolomics measured 448 metabolites. Fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15) were measured as biomarkers of mitochondrial dysfunction. The diagnostic accuracy of plasma metabolomics was over 90% (95%CI: 0.80-1.0) by area under the receiver operator characteristic (AUROC) curve analysis. Over 55% of the metabolic impact in males and 75% in females came from abnormalities in lipids. Modified purines and pyrimidines from tRNA, rRNA, and mRNA turnover were increased in the trMDD-SI group. FGF21 was increased in both males and females. Increased lactate, glutamate, and saccharopine, and decreased cystine provided evidence of reductive stress. Seventy-five percent of the metabolomic abnormalities found were individualized. Personalized deficiencies in CoQ10, flavin adenine dinucleotide (FAD), citrulline, lutein, carnitine, or folate were found. Pathways regulated by mitochondrial function dominated the metabolic signature. Peripheral blood metabolomics identified mitochondrial dysfunction and reductive stress as common denominators in suicidal ideation associated with treatment-refractory major depressive disorder. Individualized metabolic differences were found that may help with personalized management.
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Trastorno Depresivo Mayor , Enfermedades Mitocondriales , Masculino , Femenino , Humanos , Adulto , Ideación Suicida , Trastorno Depresivo Mayor/diagnóstico , Luteína , BiomarcadoresRESUMEN
Spinal muscular atrophy (SMA) is a neuromuscular genetic disorder caused by the loss of lower motor neurons leading to progressive muscle weakness and atrophy. With the rise of novel therapies and early diagnosis on newborn screening (NBS), the natural history of SMA has been evolving. Earlier therapeutic interventions can modify disease outcomes and improve survival. The role of treatment in infants born preterm is an important question given the importance of early intervention. In this study, we discuss the case of an infant born at 32 weeks who was diagnosed with SMA on NBS and was treated with Spinraza® (Nusinersen) and Zolgensma® (Onasemnogene abeparvovec-xioi) within the first 2 months of life. With the scarce evidence that currently exists, clinicians should be aware of the efficacy and safety impact of early therapy particularly in the preterm infant.
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Peripheral nerve injuries due to mass effect from bony lesions can occur when the nerve exists in an anatomically constrained location, such as the common peroneal nerve at the fibular head which passes into the tight fascia of the lateral leg compartment. We report a case of a pediatric patient who developed a common peroneal nerve palsy secondary to an osteochondroma of the fibular head and describe the clinical evaluation, radiographic findings, and surgical approach. Rapid diagnosis and nerve decompression after the onset of symptoms restored full motor function at the 8-month postoperative mark.
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Neoplasias Óseas , Osteocondroma , Neuropatías Peroneas , Humanos , Niño , Nervio Peroneo/diagnóstico por imagen , Nervio Peroneo/cirugía , Nervio Peroneo/lesiones , Peroné/diagnóstico por imagen , Peroné/cirugía , Peroné/patología , Neuropatías Peroneas/diagnóstico por imagen , Neuropatías Peroneas/etiología , Neuropatías Peroneas/cirugía , Osteocondroma/complicaciones , Osteocondroma/diagnóstico por imagen , Osteocondroma/cirugía , Parálisis/cirugía , Parálisis/complicaciones , Neoplasias Óseas/complicaciones , Neoplasias Óseas/diagnóstico por imagen , Neoplasias Óseas/cirugíaRESUMEN
Hormonal changes around ovulation divide the menstrual cycle (MC) into the follicular and luteal phases. In addition, oral contraceptives (OCs) have active (higher hormone) and placebo phases. Although there are some MC-based effects on various physiological outcomes, we found these differences relatively subtle and difficult to attribute to specific hormones, as estrogen and progesterone fluctuate rather than operating in a complete on/off pattern as observed in cellular or preclinical models often used to substantiate human data. A broad review reveals that the differences between the follicular and luteal phases and between OC active and placebo phases are not associated with marked differences in exercise performance and appear unlikely to influence muscular hypertrophy in response to resistance exercise training. A systematic review and meta-analysis of substrate oxidation between MC phases revealed no difference between phases in the relative carbohydrate and fat oxidation at rest and during acute aerobic exercise. Vascular differences between MC phases are also relatively small or nonexistent. Although OCs can vary in composition and androgenicity, we acknowledge that much more work remains to be done in this area; however, based on what little evidence is currently available, we do not find compelling support for the notion that OC use significantly influences exercise performance, substrate oxidation, or hypertrophy. It is important to note that the study of females requires better methodological control in many areas. Previous studies lacking such rigor have contributed to premature or incorrect conclusions regarding the effects of the MC and systemic hormones on outcomes. While we acknowledge that the evidence in certain research areas is limited, the consensus view is that the impact of the MC and OC use on various aspects of physiology is small or nonexistent.
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Anticonceptivos Orales , Ciclo Menstrual , Femenino , Humanos , Ciclo Menstrual/fisiología , Hormonas , Progesterona , HipertrofiaRESUMEN
BACKGROUND: Despite the growing recognition of the obesity crisis, its rates continue to rise. The current first-line therapies, such as dietary changes, energy restriction, and physical activity, are typically met with poor adherence. Novel nutritional interventions can address the root causes of obesity, including mitochondrial dysfunction, and facilitate weight loss. OBJECTIVE: The objective of this study was to investigate the effects of a multi-ingredient nutritional supplement designed to facilitate mitochondrial function and metabolic health outcomes over a 12 wk period. METHODS: Fifty-five overweight and/or obese participants (age (mean ± SEM): 26 ± 1; body mass index (BMI) (kg/m2): 30.5 ± 0.6) completed this double-blind, placebo-controlled clinical trial. Participants were randomized to 12 wks of daily consumption of multi-ingredient supplement (MIS; n = 28; containing 50 mg forskolin, 500 mg green coffee bean extract, 500 mg green tea extract, 500 mg beet root extract, 400 mg α-lipoic acid, 200 IU vitamin E, and 200 mg CoQ10) or control placebo (PLA, n = 27; containing microcrystalline cellulose) matched in appearance. The co-primary outcomes were bodyweight and fat mass (kg) changes. The secondary outcomes included other body composition measures, plasma markers of obesity, fatty liver disease biomarkers, resting energy metabolism, blood pressure, physical performance, and quality of life. The post-intervention differences between MIS and PLA were examined via ANCOVA which was adjusted for the respective pre-intervention variables. RESULTS: After adjustment for pre-intervention data, there was a significant difference in weight (p < 0.001) and fat mass (p < 0.001) post-intervention between the PLA and MIS treatment arms. Post-intervention weight and fat mass were significantly lower in MIS. Significant post-intervention differences corrected for baseline were found in markers of clinical biochemistry (AST, p = 0.017; ALT, p = 0.008), molecular metabolism (GDF15, p = 0.028), and extracellular vesicle-associated miRNA species miR-122 and miR-34a in MIS (p < 0.05). CONCLUSIONS: Following the 12 wks of MIS supplementation, weight and body composition significantly improved, concomitant with improvements in molecular markers of liver health and metabolism.
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MicroARNs , Sobrepeso , Humanos , Calidad de Vida , Obesidad/tratamiento farmacológico , Composición Corporal , Suplementos Dietéticos , Antioxidantes , PoliésteresRESUMEN
Whole-genome sequencing (WGS) is being increasingly utilized for the diagnosis of neurological disease by sequencing both the exome and the remaining 98 to 99% of the genetic code. In addition to more complete coverage, WGS can detect structural variants (SVs) and intronic variants (SNVs) that cannot be identified by whole exome sequencing (WES) or chromosome microarray (CMA). Other multi-omics tools, such as RNA sequencing (RNA-Seq), can be used in conjunction with WGS to functionally validate certain variants by detecting changes in gene expression and splicing. The objective of this retrospective study was to measure the diagnostic yield of duo/trio-based WGS and RNA-Seq in a cohort of 22 patients (20 families) with pediatric onset neurological phenotypes and negative or inconclusive WES results in lieu of reanalysis. WGS with RNA-Seq resulted in a definite diagnosis of an additional 25% of cases. Sixty percent of these solved cases arose from the identification of variants that were missed by WES. Variants that could not be unequivocally proven to be causative of the patients' condition were identified in an additional 5% of cases.
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Cylindrical spirals (CSs) are ultrastructurally distinct, intracytoplasmic inclusions characterized by concentrically wrapped lamellae, which are rarely found in skeletal muscle biopsies on electron microscopy (EM). CSs are often confused with other EM concentric structures including concentric laminated bodies and mitochondrial concentric cristae (MCC), due to similarities in these ultrastructures. In this study, we found CSs in 9 muscle biopsies from 9 patients, accounting for 0.5% of the biopsies examined routinely by EM. The frequency of CSs in these muscles varied from sparse and segregated to focally frequent and aggregated. CS-associated features included muscle fiber denervation atrophy in all 9 cases, fiber type grouping in 7/8 cases, tubular aggregates in 3/9 cases, and MCC in 2/9 cases. We also compared the concentric structures and highlighted their differences to distinguish CSs from other similar structures. Clinically, 8 out of 9 patients were adults aged 41-74 years and only one patient was 17 month-old. CSs were associated with several neurological diseases including Huntington's disease, amyotrophic lateral sclerosis, Mitochondrial Encephalopathy, Lactic Acidosis, and Stroke-like episodes, and other complex neurological disorders with neuropathy/encephalopathy, as well as anti-MDA5+ dermatomyositis. Eight of nine patients had genetic findings such as trinucleotide repeat expansion of huntingtin gene, ALS2 variant, MT-TL1 m.3243A > G mutation, and PMP 22 gene deletion. These results suggest that CSs may be highly variable in frequency and likely are under-reported/under-detected; they may be associated with neurogenic myopathy or central/peripheral nervous system disorders including some genetic neurological/neuromuscular diseases. Our findings of more CS-associated neurological diseases and an association of CSs with muscle neurogenic features may contribute to a better understanding of the clinico-pathological significance of CSs.
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Enfermedad de Huntington , Enfermedades Musculares , Enfermedades Neuromusculares , Adulto , Humanos , Lactante , Músculo Esquelético/patología , Enfermedades Musculares/patología , Enfermedad de Huntington/patología , Atrofia Muscular/patologíaRESUMEN
The study objective is to evaluate the influence of attrition from a paediatric weight management program (PWM) on health indicators over a 2-year period. In this observational study, children and youth with obesity were recruited at entry into a family-based behaviour modification PWM and had four research study visits, independent of clinic visits, over 2 years. Participants were divided into attrition groups based on length of clinic enrolment. Body composition, cardiometabolic health and health-related quality of life (HRQoL) were assessed. Among 269 children enrolled, 19% had no clinic treatment visit, 16% had treatment visits only up to 6 months, 23% up to 1 year and 42% had at least one clinic visit after 1 year (No Attrition). Greater declines in BMI z-score and body fat were seen at 2 years in children with No Attrition, while improvements in HRQoL were similar for all attrition groups. Children who attended at least one treatment visit reported improved HRQoL up to 2 years, regardless of duration in clinic. In contrast, declines in body fat and BMI z-score were greater at 2 years for those with at least one visit after 1 year. Continued efforts to reduce attrition are likely to improve anthropometric health outcomes during PWM.
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Obesidad , Calidad de Vida , Adolescente , Humanos , Niño , Índice de Masa Corporal , Obesidad/terapia , Antropometría , Composición CorporalRESUMEN
BACKGROUND AND OBJECTIVES: Primary mitochondrial myopathies (PMMs) encompass a group of genetic disorders that impair mitochondrial oxidative phosphorylation, adversely affecting physical function, exercise capacity, and quality of life (QoL). Current PMM standards of care address symptoms, with limited clinical impact, constituting a significant therapeutic unmet need. We present data from MMPOWER-3, a pivotal, phase-3, randomized, double-blind, placebo-controlled clinical trial that evaluated the efficacy and safety of elamipretide in participants with genetically confirmed PMM. METHODS: After screening, eligible participants were randomized 1:1 to receive either 24 weeks of elamipretide at a dose of 40 mg/d or placebo subcutaneously. Primary efficacy endpoints included change from baseline to week 24 on the distance walked on the 6-minute walk test (6MWT) and total fatigue on the Primary Mitochondrial Myopathy Symptom Assessment (PMMSA). Secondary endpoints included most bothersome symptom score on the PMMSA, NeuroQoL Fatigue Short-Form scores, and the patient global impression and clinician global impression of PMM symptoms. RESULTS: Participants (N = 218) were randomized (n = 109 elamipretide; n = 109 placebo). The m0ean age was 45.6 years (64% women; 94% White). Most of the participants (n = 162 [74%]) had mitochondrial DNA (mtDNA) alteration, with the remainder having nuclear DNA (nDNA) defects. At screening, the most frequent bothersome PMM symptom on the PMMSA was tiredness during activities (28.9%). At baseline, the mean distance walked on the 6MWT was 336.7 ± 81.2 meters, the mean score for total fatigue on the PMMSA was 10.6 ± 2.5, and the mean T score for the Neuro-QoL Fatigue Short-Form was 54.7 ± 7.5. The study did not meet its primary endpoints assessing changes in the 6MWT and PMMSA total fatigue score (TFS). Between the participants receiving elamipretide and those receiving placebo, the difference in the least squares mean (SE) from baseline to week 24 on distance walked on the 6MWT was -3.2 (95% CI -18.7 to 12.3; p = 0.69) meters, and on the PMMSA, the total fatigue score was -0.07 (95% CI -0.10 to 0.26; p = 0.37). Elamipretide treatment was well-tolerated with most adverse events being mild to moderate in severity. DISCUSSION: Subcutaneous elamipretide treatment did not improve outcomes in the 6MWT and PMMSA TFS in patients with PMM. However, this phase-3 study demonstrated that subcutaneous elamipretide is well-tolerated. TRIAL REGISTRATION INFORMATION: Trial registered with clinicaltrials.gov, Clinical Trials Identifier: NCT03323749; submitted on October 12, 2017; first patient enrolled October 9, 2017. CLINICALTRIALS: gov/ct2/show/NCT03323749?term = elamipretide&draw = 2&rank = 9. CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that elamipretide does not improve the 6MWT or fatigue at 24 weeks compared with placebo in patients with primary mitochondrial myopathy.
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Miopatías Mitocondriales , Calidad de Vida , Humanos , Femenino , Persona de Mediana Edad , Masculino , Proteína 1 de Superficie de Merozoito/uso terapéutico , Miopatías Mitocondriales/tratamiento farmacológico , Fatiga , Método Doble Ciego , Resultado del TratamientoRESUMEN
OBJECTIVE: Metabolic Syndrome (MetS) affects hundreds of millions of individuals and constitutes a major cause of morbidity and mortality worldwide. Obesity is believed to be at the core of metabolic abnormalities associated with MetS, including dyslipidemia, insulin resistance, fatty liver disease and vascular dysfunction. Although previous studies demonstrate a diverse array of naturally occurring antioxidants that attenuate several manifestations of MetS, little is known about the (i) combined effect of these compounds on hepatic health and (ii) molecular mechanisms responsible for their effect. METHODS: We explored the impact of a metabolic enhancer (ME), consisting of 7 naturally occurring antioxidants and mitochondrial enhancing agents, on diet-induced obesity, hepatic steatosis and atherogenic serum profile in mice. RESULTS: Here we show that a diet-based ME supplementation and exercise have similar beneficial effects on adiposity and hepatic steatosis in mice. Mechanistically, ME reduced hepatic ER stress, fibrosis, apoptosis, and inflammation, thereby improving overall liver health. Furthermore, we demonstrated that ME improved HFD-induced pro-atherogenic serum profile in mice, similar to exercise. The protective effects of ME were reduced in proprotein convertase subtilisin/kexin 9 (PCSK9) knock out mice, suggesting that ME exerts it protective effect partly in a PCSK9-dependent manner. CONCLUSIONS: Our findings suggest that components of the ME have a positive, protective effect on obesity, hepatic steatosis and cardiovascular risk and that they show similar effects as exercise training.
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Resistencia a la Insulina , Síndrome Metabólico , Enfermedad del Hígado Graso no Alcohólico , Ratones , Animales , Proproteína Convertasa 9/metabolismo , Antioxidantes/metabolismo , Dieta Alta en Grasa/efectos adversos , Obesidad/metabolismo , Hígado/metabolismo , Síndrome Metabólico/etiología , Síndrome Metabólico/prevención & control , Síndrome Metabólico/metabolismo , Enfermedad del Hígado Graso no Alcohólico/etiología , Enfermedad del Hígado Graso no Alcohólico/prevención & control , Enfermedad del Hígado Graso no Alcohólico/metabolismo , Ratones Endogámicos C57BLRESUMEN
OBJECTIVE: ST3GAL3-related developmental and epileptic encephalopathy (DEE-15) is an autosomal recessive condition characterized by intellectual disability, language and motor impairments, behavioral difficulties, stereotypies, and epilepsy. Only a few cases have been reported, and the epilepsy phenotype is not fully elucidated. METHODS: A retrospective chart review of two siblings with ST3GAL3-related DEE was completed. In addition, we reviewed all published cases of ST3GAL3-related congenital disorder of glycosylation. RESULTS: Two brothers presented with global developmental delay, motor and language impairment, hypotonia, and childhood-onset seizures. Seizures started between 2.5 and 5 years and had tonic components. Both siblings had prolonged periods of seizure freedom on carbamazepine. Tremor was present in the younger sibling. Whole exome sequencing revealed two novel pathogenic variants in ST3GAL3, (a) c.302del, p.Phe102Serfs*34 and (b) c.781C>T, p.Arg261*, which were inherited in trans. Magnetic resonance imaging showed T2 hyperintensities and restricted diffusion in the brainstem and middle cerebellar peduncle in the older sibling, also described in two reported cases. A review of the literature revealed 24 cases of ST3GAL3-related CDG. Twelve cases had information about seizures, and epilepsy was diagnosed in 8 (67%). The median age of seizure onset was 5.5 months. Epileptic spasms were most common (67%). Four children were diagnosed with Infantile Epileptic Spasms syndrome and Lennox Gastaut syndrome (57%). Most children (n = 6, 75%) had seizures despite anti-seizure medication treatment. SIGNIFICANCE: Seizures related to ST3GAL3-related DEE often occur in infancy and may present as epileptic spasms. However, seizure onset may also occur outside of infancy with mixed seizure types and show good response to treatment with prolonged seizure freedom. Tremor may also be uniquely observed in this condition.
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Epilepsia , Espasmos Infantiles , Humanos , Masculino , Epilepsia/genética , Epilepsia/diagnóstico , Fenotipo , Estudios Retrospectivos , Espasmo , Espasmos Infantiles/genética , TemblorRESUMEN
The age-related loss of skeletal muscle mass and functionality, known as sarcopenia, is a critical risk factor for morbidity and all-cause mortality. Resistance exercise training (RET) is the primary countermeasure to fight sarcopenia and ageing. Altered intercellular communication is a hallmark of ageing, which is not well elucidated. Circulating extracellular vesicles (EVs), including exosomes, contribute to intercellular communication by delivering microRNAs (miRNAs), which modulate post-translational modifications, and have been shown to be released following exercise. There is little evidence regarding how EVs or EV-miRNAs are altered with age or RET. Therefore, we sought to characterize circulating EVs in young and older individuals, prior to and following a 12-week resistance exercise programme. Plasma EVs were isolated using size exclusion chromatography and ultracentrifugation. We found that ageing reduced circulating expression markers of CD9, and CD81. Using late-passage human myotubes as a model for ageing in vitro, we show significantly lower secreted exosome-like vesicles (ELVs). Further, levels of circulating ELV-miRNAs associated with muscle health were lower in older individuals at baseline but increased following RET to levels comparable to young. Muscle biopsies show similar age-related reductions in miRNA expressions, with largely no effect of training. This is reflected in vitro, where aged myotubes show significantly reduced expression of endogenous and secreted muscle-specific miRNAs (myomiRs). Lastly, proteins associated with ELV and miRNA biogenesis were significantly higher in both older skeletal muscle tissues and aged human myotubes. Together we show that ageing significantly affects ELV and miRNA cargo biogenesis, and release. RET can partially normalize this altered intercellular communication. KEY POINTS: We show that ageing reduces circulating expression of exosome-like vesicle (ELV) markers, CD9 and CD81. Using late-passage human skeletal myotubes as a model of ageing, we show that secreted ELV markers are significantly reduced in vitro. We find circulating ELV miRNAs associated with skeletal muscle health are lower in older individuals but can increase following resistance exercise training (RET). In skeletal muscle, we find altered expression of miRNAs in older individuals, with no effect of RET. Late-passage myotubes also appear to have aberrant production of endogenous myomiRs with lower abundance than youthful counterparts In older skeletal muscle and late-passage myotubes, proteins involved with ELV- and miRNA biogenesis are upregulated.