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1.
Vet Clin North Am Equine Pract ; 36(2): 353-378, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32654785

RESUMO

There are 5 single-gene mutations that are known to cause muscle disease in horses. These mutations alter the amino acid sequence of proteins involved in cell membrane electrical conduction, muscle energy metabolism, muscle contraction, and immunogenicity. The clinical signs depend on the pathway affected. The likelihood that an animal with a mutation will exhibit clinical signs depends on the mode of inheritance, environmental influences, and interactions with other genes. Selection of a genetic test for use in diagnostic or breeding decisions requires a knowledge of clinical signs, mode of inheritance, breeds affected, and proper scientific test validation.


Assuntos
Doenças dos Cavalos/genética , Doenças Musculares/veterinária , Animais , Doenças dos Cavalos/metabolismo , Cavalos , Doenças Musculares/genética , Doenças Musculares/metabolismo
2.
PLoS One ; 15(7): e0235702, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32634159

RESUMO

Rheumatoid arthritis (RA) is accompanied by pain, inflammation and muscle weakness. Skeletal muscle inflammation and inactivity are independently associated with muscle insulin resistance and atrophy. Our objective was to identify early molecular and biochemical markers in muscle from a rodent model of RA relative to control and subsequently identify commonality in muscle gene expression between this model and muscle from RA patients. Pain behaviour and locomotor activity were measured in a collagen-induced arthritis (CIA) model of RA (n = 9) and control (n = 9) rats. Energy substrates and metabolites, total alkaline-soluble protein:DNA ratio and mRNA abundance of 46 targeted genes were also determined in Extensor digitorum longus muscle. Expression of targeted mRNAs was quantified in Vastus Lateralis muscle from RA patients (n = 7) and healthy age-matched control volunteers (n = 6). CIA rats exhibited pain behaviour (p<0.01) and reduced activity (p<0.05) compared to controls. Muscle glycogen content was less (p<0.05) and muscle lactate content greater (p<0.01) in CIA rats. The bioinformatics analysis of muscle mRNA abundance differences from the control, predicted the activation of muscle protein metabolism and inhibition of muscle carbohydrate and fatty acid metabolism in CIA rats. Compared to age-matched control volunteers, RA patients exhibited altered muscle mRNA expression of 8 of the transcripts included as targets in the CIA model of RA. In conclusion, muscle energy metabolism and metabolic gene expression were altered in the CIA model, which was partly corroborated by targeted muscle mRNA measurements in RA patients. This research highlights the negative impact of RA on skeletal muscle metabolic homeostasis.


Assuntos
Artrite Reumatoide/complicações , Músculo Esquelético/metabolismo , Doenças Musculares/etiologia , Idoso , Animais , Artrite Experimental/metabolismo , Artrite Reumatoide/metabolismo , Biomarcadores , Modelos Animais de Doenças , Feminino , Glicogênio/metabolismo , Humanos , Inflamação , Locomoção , Pessoa de Meia-Idade , Doenças Musculares/metabolismo , Mialgia/etiologia , RNA Mensageiro/metabolismo , Ratos , Ratos Endogâmicos Lew , Transcriptoma
3.
Neurol Clin ; 38(3): 619-635, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32703473

RESUMO

Healthy muscle relies on a complex and interdependent network that includes, but is not limited to, proteins, ion channels, and the production and utilization of ATP. Disruptions to the system can occur for a number of reasons (genetic mutations, toxins, systemic disease, inflammation), yet they clinically present with symptoms that are nonspecific and common to myopathies: weakness, muscle pain, cramping, hypotonia. This article uses a case-based format to review the clinical reasoning and diagnostic tools that guide the accurate diagnosis of myopathies. We specifically focus on toxic, metabolic, mitochondrial, and late-onset congenital myopathies.


Assuntos
Doenças Musculares/diagnóstico , Doenças Musculares/metabolismo , Mutação/genética , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miopatias Mitocondriais/diagnóstico , Miopatias Mitocondriais/genética , Miopatias Mitocondriais/metabolismo , Debilidade Muscular/diagnóstico , Debilidade Muscular/genética , Debilidade Muscular/metabolismo , Doenças Musculares/genética , Mialgia/diagnóstico , Mialgia/genética , Mialgia/metabolismo
5.
Toxicol Appl Pharmacol ; 401: 115076, 2020 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-32479918

RESUMO

Statin induced myopathy (SIM) is a main deleterious effect leading to the poor treatment compliance, while the preventive or therapeutic treatments are absent. Mounting evidences demonstrated that vitamin D plays a vital role in muscle as a direct modulator. The deficiency of vitamin D was considered as a cause of muscle dysfunction, whereas the supplementation resulted in a remission. However, there is no causal proof that vitamin D supplementation rescues SIM. Here, using the mice model of simvastatin-induced myopathy, we investigated the role of vitamin D supplementation and the mechanisms associated with mitochondria. Results indicated that simvastatin administration (80 mg/kg) impaired skeletal muscle with the increased serum creatine kinase (CK) level and the declined grip strength, which were alleviated by vitamin D supplementation. Moreover, vitamin D supplementation rescued the energy metabolism dysfunction in simvastatin-treated mice gastrocnemius by reducing the abnormal aggregation of muscular glycogen and lactic acid. Mitochondrial homeostasis plays a key role in the process of energy metabolism. Thus, the mitochondrial dysfunction is a mortal damage for the highly energy-requiring tissue. In our study, the mitochondrial cristae observed under transmission electron microscope (TEM) were lytic in simvastatin-treated gastrocnemius. Interestingly, vitamin D supplementation improved the mitochondrial cristae shape by regulating the expression of mitofusin-1/2 (MFN1/2), optic atrophy 1 (OPA1) and dynamin-related protein 1 (Drp1). As expected, the mitochondrial dysfunction and oxidative stress was mitigated by vitamin D supplementation. In conclusion, these findings suggested that moderate vitamin D supplementation rescued simvastatin induced myopathy via improving the mitochondrial cristae shape and function.


Assuntos
Suplementos Nutricionais , Mitocôndrias/efeitos dos fármacos , Doenças Musculares/induzido quimicamente , Doenças Musculares/tratamento farmacológico , Sinvastatina/toxicidade , Vitamina D/administração & dosagem , Animais , Metabolismo Energético/efeitos dos fármacos , Metabolismo Energético/fisiologia , Inibidores de Hidroximetilglutaril-CoA Redutases/toxicidade , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Membranas Mitocondriais/efeitos dos fármacos , Membranas Mitocondriais/metabolismo , Membranas Mitocondriais/patologia , Doenças Musculares/metabolismo , Distribuição Aleatória
6.
Psychopharmacology (Berl) ; 237(8): 2367-2380, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32445052

RESUMO

RATIONALE: Proinflammatory processes have been implicated in alcohol addiction, craving, and relapse, while studies in experimental animals have suggested that activation of peroxisome proliferator-activated receptor gamma (PPARγ) inhibits proinflammatory signaling. Accordingly, it is hypothesized that medications with PPARγ activity may have therapeutic potential in alcohol dependence. OBJECTIVES: We conducted a double-blind, placebo-controlled mechanistic proof of principle study in alcohol-dependent inpatients to investigate the effect of pioglitazone on alcohol craving. METHODS: Participants were treated for withdrawal, if needed, and then randomized to pioglitazone (target dose 45 mg/day) or placebo. Once at target dose, they completed two experimental manipulations: guided imagery, which used personalized auditory scripts to induce alcohol cravings, and a low-dose challenge with i.v. lipopolysaccharide (LPS; 0.8 ng/kg) or placebo, on two separate sessions, in counterbalanced order. Behavioral and endocrine responses as well as CSF levels of proinflammatory cytokines were evaluated. RESULTS: The study was prematurely terminated after randomization of 16 subjects, following an independent review that established a high risk of myopathy in the active treatment group. Analysis of those who completed the study indicated that pioglitazone was associated with elevated, rather than suppressed alcohol cravings in response to alcohol-associated stimuli. LPS did not induce cravings for alcohol and thus did not lend itself to evaluating pioglitazone effects; however, pioglitazone increased the neuroendocrine stress response to LPS. CSF levels of IL-6, TNF-α, or MCP-1 were unaffected by pioglitazone treatment. CONCLUSIONS: Both safety and efficacy biomarker data suggest that pioglitazone lacks potential as a medication for the treatment of alcohol dependence. CLINICAL TRIAL REGISTRATION: NCT01631630.


Assuntos
Alcoolismo/metabolismo , Fissura/efeitos dos fármacos , Doenças Musculares/induzido quimicamente , Doenças Musculares/metabolismo , PPAR gama/metabolismo , Pioglitazona/uso terapêutico , Adulto , Alcoolismo/tratamento farmacológico , Animais , Fissura/fisiologia , Método Duplo-Cego , Feminino , Humanos , Hipoglicemiantes/efeitos adversos , Hipoglicemiantes/uso terapêutico , Imaginação/efeitos dos fármacos , Imaginação/fisiologia , Lipopolissacarídeos/efeitos adversos , Masculino , Pessoa de Meia-Idade , Doenças Musculares/diagnóstico , Pioglitazona/efeitos adversos , Estudo de Prova de Conceito , Recidiva , Adulto Jovem
7.
ScientificWorldJournal ; 2020: 4704825, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32292293

RESUMO

Objectives: Statin-induced myopathy is one of the major causes of poor adherence and discontinuation of this medication. There are contrary results regarding association of vitamin D insufficiency with statin-induced myopathy. This study was done to determine the effect of the vitamin D3 analogue alfacalcidol on Rosuvastatin-induced myopathy in rats. Methodology. Animals were divided into six groups with 6 rats in each group. Groups I and II acted as controls, Group III and Group IV were administered Rosuvastatin 120 mg/kg/day and 160 mg/kg/day, Groups V and VI were administered alfacalcidol 0.1 µg/kg/day in addition to Rosuvastatin 120 mg/kg/day and 160 mg/kg/day, respectively. All drugs were administered orally for 15 days. Plasma creatine kinase (CK) levels were estimated on day 10 and day 15. Animals were sacrificed and muscles were sent for histopathological examination. Results: On day 10, Groups V and VI showed a statistically significant increase in plasma CK levels as compared to the control (p < 0.001) and were significantly lower (p < 0.001) as compared to Groups III and IV, respectively. However, on day 15, plasma CK levels in Groups V and VI were comparable to those of control groups with a nonsignificant difference (p > 0.05). On comparing the histology, Groups V and VI showed a significant difference as compared to statin-only groups (Groups III and IV) as there were signs of regeneration, less splitting, and fragmentation of muscle fibres. Conclusion: The present study shows that the vitamin D analogue alfacalcidol prevents statin-induced myopathy. The serum CK levels are comparable to the control group on day 15 of vitamin D administration.


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/efeitos adversos , Doenças Musculares/etiologia , Doenças Musculares/metabolismo , Rosuvastatina Cálcica/efeitos adversos , Vitamina D/metabolismo , Animais , Biomarcadores , Biópsia , Creatina Quinase/sangue , Modelos Animais de Doenças , Doenças Musculares/sangue , Doenças Musculares/patologia , Ratos , Ratos Wistar , Vitamina D/análogos & derivados , Deficiência de Vitamina D/complicações
9.
Cancer Res ; 80(9): 1861-1874, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-32132110

RESUMO

Skeletal muscle wasting is a devastating consequence of cancer that contributes to increased complications and poor survival, but is not well understood at the molecular level. Herein, we investigated the role of Myocilin (Myoc), a skeletal muscle hypertrophy-promoting protein that we showed is downregulated in multiple mouse models of cancer cachexia. Loss of Myoc alone was sufficient to induce phenotypes identified in mouse models of cancer cachexia, including muscle fiber atrophy, sarcolemmal fragility, and impaired muscle regeneration. By 18 months of age, mice deficient in Myoc showed significant skeletal muscle remodeling, characterized by increased fat and collagen deposition compared with wild-type mice, thus also supporting Myoc as a regulator of muscle quality. In cancer cachexia models, maintaining skeletal muscle expression of Myoc significantly attenuated muscle loss, while mice lacking Myoc showed enhanced muscle wasting. Furthermore, we identified the myocyte enhancer factor 2 C (MEF2C) transcription factor as a key upstream activator of Myoc whose gain of function significantly deterred cancer-induced muscle wasting and dysfunction in a preclinical model of pancreatic ductal adenocarcinoma (PDAC). Finally, compared with noncancer control patients, MYOC was significantly reduced in skeletal muscle of patients with PDAC defined as cachectic and correlated with MEF2c. These data therefore identify disruptions in MEF2c-dependent transcription of Myoc as a novel mechanism of cancer-associated muscle wasting that is similarly disrupted in muscle of patients with cachectic cancer. SIGNIFICANCE: This work identifies a novel transcriptional mechanism that mediates skeletal muscle wasting in murine models of cancer cachexia that is disrupted in skeletal muscle of patients with cancer exhibiting cachexia.


Assuntos
Caquexia/complicações , Proteínas do Citoesqueleto/metabolismo , Proteínas do Olho/metabolismo , Glicoproteínas/metabolismo , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Síndrome de Emaciação/etiologia , Animais , Composição Corporal , Caquexia/metabolismo , Carcinoma Ductal Pancreático/complicações , Carcinoma Ductal Pancreático/metabolismo , Proteínas do Citoesqueleto/deficiência , Proteínas do Citoesqueleto/genética , Diafragma/fisiologia , Modelos Animais de Doenças , Regulação para Baixo , Proteínas do Olho/genética , Feminino , Glicoproteínas/deficiência , Glicoproteínas/genética , Xenoenxertos , Humanos , Fatores de Transcrição MEF2/metabolismo , Masculino , Camundongos , Músculo Esquelético/patologia , Atrofia Muscular , Doenças Musculares/etiologia , Proteínas de Neoplasias/metabolismo , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/metabolismo , RNA Mensageiro/metabolismo , Regeneração , Corrida , Sarcolema , Síndrome de Emaciação/metabolismo , Síndrome de Emaciação/prevenção & controle
10.
Am J Physiol Cell Physiol ; 318(4): C709-C718, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32023076

RESUMO

This review analyzes data concerning patients with cardiomyopathies or skeletal myopathies associated with a variation in the intermediate filament (IF) synemin gene (SYNM), also referred to as desmuslin (DMN). Molecular studies demonstrate that synemin copolymerizes with desmin and vimentin IF and interacts with vinculin, α-actinin, α-dystrobrevin, dystrophin, talin, and zyxin. It has been found that synemin is an A-kinase-anchoring protein (AKAP) that anchors protein kinase A (PKA) and modulates the PKA-dependent phosphorylation of several cytoskeletal substrates such as desmin. Because several IF proteins, including desmin, have been implicated in human genetic disorders such as dominant or recessive congenital and adult-onset myopathy, synemin becomes a significant candidate for cardiac and skeletal myopathies of unknown etiology. Because SYNM is a new candidate gene that displays numerous sequence polymorphisms, in this review, we summarize the genetic and clinical literature about SYNM mutations. Protein-changing variants (missense, frameshifts, nonsense) were further evaluated based on structural modifications and amino acid interactions. We present in silico modeling of helical salt-bridges between residues to evaluate the impact of the synemin networks crucial to interactions with cytoskeletal proteins. Finally, a discussion is featured regarding certain variants that may contribute to the disease state.


Assuntos
Citoesqueleto/patologia , Proteínas de Filamentos Intermediários/metabolismo , Proteínas Musculares/metabolismo , Doenças Musculares/metabolismo , Animais , Citoesqueleto/metabolismo , Coração/fisiopatologia , Humanos , Filamentos Intermediários/metabolismo , Doenças Musculares/patologia
12.
Biochim Biophys Acta Mol Basis Dis ; 1866(6): 165745, 2020 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-32105824

RESUMO

Desmin, being a major intermediate filament of muscle cells, contributes to stabilization and positioning of mitochondria. Desmin mutations have been reported in conjunction with skeletal myopathies accompanied by mitochondrial dysfunction. Depending on the ability to promote intracellular aggregates formation, mutations can be considered aggregate-prone or non-aggregate-prone. The aim of the present study was to describe how expression of different desmin mutant isoforms effects mitochondria and contributes to the development of myocyte dysfunction. To achieve this goal, two non-aggregate-prone (Des S12F and Des A213V) and four aggregate-prone (Des L345P, Des A357P, Des L370P, Des D399Y) desmin mutations were expressed in skeletal muscle cells. We showed that all evaluated mutations affected the morphology of mitochondrial network, suppressed parameters of mitochondrial respiration, diminished mitochondrial membrane potential, increased ADP/ATP ratio, and enhanced mitochondrial DNA (mtDNA) release. mtDNA was partially secreted through exosomes as demonstrated by GW4869 treatment. Dysfunction of mitochondria was observed regardless the type of mutation: aggregate-prone or non-aggregate-prone. However, expression of aggregate-prone mutations resulted in more prominent phenotype. Thus, in this comparative study of six pathogenic desmin mutations that cause skeletal myopathy development, we confirmed a role of mitochondrial dysfunction and mtDNA release in the pathogenesis of desmin myopathies, regardless of the aggregation capacity of the mutated desmin.


Assuntos
Desmina/genética , Mitocôndrias/genética , Doenças Musculares/genética , Agregados Proteicos/genética , DNA Mitocondrial/genética , Desmina/classificação , Regulação da Expressão Gênica/genética , Humanos , Filamentos Intermediários/metabolismo , Filamentos Intermediários/patologia , Mitocôndrias/metabolismo , Mitocôndrias/patologia , Células Musculares/metabolismo , Células Musculares/patologia , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Doenças Musculares/metabolismo , Doenças Musculares/patologia , Mutação/genética , Fenótipo
13.
Int J Mol Sci ; 21(2)2020 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-31952119

RESUMO

Sarcomere assembly and maintenance are essential physiological processes required for cardiac and skeletal muscle function and organism mobility. Over decades of research, components of the sarcomere and factors involved in the formation and maintenance of this contractile unit have been identified. Although we have a general understanding of sarcomere assembly and maintenance, much less is known about the development of the thin filaments and associated factors within the sarcomere. In the last decade, advancements in medical intervention and genome sequencing have uncovered patients with novel mutations in sarcomere thin filaments. Pairing this sequencing with reverse genetics and the ability to generate patient avatars in model organisms has begun to deepen our understanding of sarcomere thin filament development. In this review, we provide a summary of recent findings regarding sarcomere assembly, maintenance, and disease with respect to thin filaments, building on the previous knowledge in the field. We highlight debated and unknown areas within these processes to clearly define open research questions.


Assuntos
Citoesqueleto de Actina/genética , Contração Muscular/genética , Doenças Musculares/genética , Sarcômeros/genética , Citoesqueleto de Actina/metabolismo , Animais , Humanos , Proteínas Musculares/genética , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Doenças Musculares/metabolismo , Mutação , Sarcômeros/metabolismo , Sequenciamento Completo do Genoma/métodos
14.
FASEB J ; 34(1): 1755-1767, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31914685

RESUMO

Patients with chronic kidney disease (CKD) exhibit reduced exercise capacity, poor physical function and symptoms of fatigue. The mechanisms that contribute to this are not clearly defined but may involve reductions in mitochondrial function, mass and biogenesis. Here we report on the effect of non-dialysis dependent CKD (NDD-CKD) on mitochondrial mass and basal expression of transcription factors involved in mitochondrial biogenesis compared to a healthy control cohort (HC). In addition, we sought to investigate the effect of a 12-week exercise-training programme on these aspects of mitochondrial dysfunction in a NDD-CKD cohort.For the comparison between NDD-CKD and HC populations, skeletal muscle biopsies were collected from the vastus lateralis (VL) of n=16 non-dialysis dependent CKD patient's stage 3b-5 (NDD-CKD) and n=16 healthy controls matched for age, gender and physical activity (HC). To investigate the effect of exercise training, VL biopsies were collected from n=17 NDD-CKD patients before and after a 12-week exercise intervention that was comprised of aerobic exercise (AE) or a combination of aerobic exercise and resistance training (CE). Mitochondrial mass was analysed by citrate synthase activity and mitochondrial protein content by Porin expression, whilst the expression of transcription factors involved in mitochondrial biogenesis were quantified by real-time qPCR. NDD-CKD patients exhibited a significant reduction in mitochondrial mass when compared to HC, coupled to a reduction in PGC-1α, NRF-1, Nrf2, TFam, mfn2 and SOD1/2 gene expression. 12-weeks of exercise training resulted in a significant increase in PGC-1α expression in both groups, with no further changes seen across indicators of mitochondrial biogenesis. No significant changes in mitochondrial mass were observed in response to either exercise programme. NDD-CKD patients exhibit reduced skeletal muscle mitochondrial mass and gene expression of transcription factors involved in mitochondrial biogenesis compared to HC. These reductions were not restored following 12-weeks of exercise training implying exercise resistance in this cohort. The reasons for this lack of improvement are currently unknown and require further investigation, as reversing the dysregulation of these processes in NDD-CKD may provide a therapeutic opportunity to improve muscle fatigue and dysfunction in this population.


Assuntos
Exercício Físico/fisiologia , Mitocôndrias Musculares/fisiologia , Músculo Esquelético/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Estudos Transversais , Feminino , Expressão Gênica/fisiologia , Humanos , Masculino , Pessoa de Meia-Idade , Mitocôndrias Musculares/metabolismo , Proteínas Mitocondriais/metabolismo , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Doenças Musculares/fisiopatologia , Estudos Observacionais como Assunto , Biogênese de Organelas , Músculo Quadríceps/metabolismo , Músculo Quadríceps/fisiologia , Treinamento de Resistência/métodos
15.
Genet Med ; 22(1): 112-123, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31273343

RESUMO

PURPOSE: To date, heterozygous or homozygous COL12A1 variants have been reported in 13 patients presenting with a clinical phenotype overlapping with collagen VI-related myopathies and Ehlers-Danlos syndrome (EDS). The small number of reported patients limits thorough investigation of this newly identified syndrome, currently coined as myopathic EDS. METHODS: DNA from 78 genetically unresolved patients fulfilling the clinical criteria for myopathic EDS was sequenced using a next-generation panel of COL12A1, COL6A1, COL6A2, and COL6A3. RESULTS: Among this cohort, we identified four pathogenic heterozygous in-frame exon skipping (∆) defects in COL12A1, clustering to the thrombospondin N-terminal region and the adjacent collagenous domain (Δ52, Δ53, Δ54, and Δ56 respectively), one heterozygous COL12A1 arginine-to-cysteine substitution of unclear significance (p.(Arg1863Cys)), and compound heterozygous pathogenic COL6A1 variants (c.[98-6G>A];[301C>T]) in one proband. Variant-specific intracellular accumulation of collagen XII chains, extracellular overmodification of the long isoform and near-absence of the short isoform of collagen XII, and extracellular decrease of decorin and tenascin-X were observed for the COL12A1 variants. In contrast, the COL6A1 variants abolished collagen VI and V deposition and increased tenascin-X levels. CONCLUSION: Our data further support the significant clinical overlap between myopathic EDS and collagen VI-related myopathies, and emphasize the variant-specific consequences of collagen XII defects.


Assuntos
Colágeno Tipo VI/genética , Colágeno Tipo XII/genética , Síndrome de Ehlers-Danlos/genética , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Doenças Musculares/genética , Mutação , Adolescente , Adulto , Células Cultivadas , Criança , Pré-Escolar , Colágeno Tipo V/metabolismo , Colágeno Tipo VI/química , Colágeno Tipo XII/química , Decorina/metabolismo , Síndrome de Ehlers-Danlos/metabolismo , Matriz Extracelular/metabolismo , Feminino , Humanos , Masculino , Doenças Musculares/metabolismo , Linhagem , Domínios Proteicos , Análise de Sequência de DNA , Tenascina/metabolismo
16.
Am J Physiol Cell Physiol ; 318(1): C1-C28, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31483703

RESUMO

Although a majority of the mammalian genome is transcribed to RNA, mounting evidence indicates that only a minor proportion of these transcriptional products are actually translated into proteins. Since the discovery of the first non-coding RNA (ncRNA) in the 1980s, the field has gone on to recognize ncRNAs as important molecular regulators of RNA activity and protein function, knowledge of which has stimulated the expansion of a scientific field that quests to understand the role of ncRNAs in cellular physiology, tissue homeostasis, and human disease. Although our knowledge of these molecules has significantly improved over the years, we have limited understanding of their precise functions, protein interacting partners, and tissue-specific activities. Adding to this complexity, it remains unknown exactly how many ncRNAs there are in existence. The increased use of high-throughput transcriptomics techniques has rapidly expanded the list of ncRNAs, which now includes classical ncRNAs (e.g., ribosomal RNAs and transfer RNAs), microRNAs, and long ncRNAs. In addition, splicing by-products of protein-coding genes and ncRNAs, so-called circular RNAs, are now being investigated. Because there is substantial heterogeneity in the functions of ncRNAs, we have summarized the present state of knowledge regarding the functions of ncRNAs in heart, lungs, and skeletal muscle. This review highlights the pathophysiologic relevance of these ncRNAs in the context of human cardiovascular, pulmonary, and muscle diseases.


Assuntos
Doenças Cardiovasculares/genética , Pneumopatias/genética , Doenças Musculares/genética , RNA não Traduzido/genética , Animais , Doenças Cardiovasculares/diagnóstico , Doenças Cardiovasculares/metabolismo , Doenças Cardiovasculares/fisiopatologia , Regulação da Expressão Gênica , Marcadores Genéticos , Humanos , Pneumopatias/diagnóstico , Pneumopatias/metabolismo , Pneumopatias/fisiopatologia , Doenças Musculares/diagnóstico , Doenças Musculares/metabolismo , Doenças Musculares/fisiopatologia , Valor Preditivo dos Testes , RNA não Traduzido/metabolismo , Transdução de Sinais
17.
Am J Respir Crit Care Med ; 201(2): 148-157, 2020 01 15.
Artigo em Inglês | MEDLINE | ID: mdl-31513751

RESUMO

Pulmonary arterial hypertension (PAH) is a disease characterized by progressive loss and remodeling of the pulmonary arteries, resulting in right heart failure and death. Until recently, PAH was seen as a disease restricted to the pulmonary circulation. However, there is growing evidence that patients with PAH also exhibit systemic vascular dysfunction, as evidenced by impaired brachial artery flow-mediated dilation, abnormal cerebral blood flow, skeletal myopathy, and intrinsic kidney disease. Although some of these anomalies are partially due to right ventricular insufficiency, recent data support a mechanistic link to the genetic and molecular events behind PAH pathogenesis. This review serves as an introduction to the major systemic findings in PAH and the evidence that supports a common mechanistic link with PAH pathophysiology. In addition, it discusses recent studies describing morphological changes in systemic vessels and the possible role of bronchopulmonary anastomoses in the development of plexogenic arteriopathy. On the basis of available evidence, we propose a paradigm in which metabolic abnormalities, genetic injury, and systemic vascular dysfunction contribute to systemic manifestations in PAH. This concept not only opens exciting research possibilities but also encourages clinicians to consider extrapulmonary manifestations in their management of patients with PAH.


Assuntos
Transtornos Cerebrovasculares/fisiopatologia , Doença da Artéria Coronariana/fisiopatologia , Nefropatias/fisiopatologia , Doenças Musculares/fisiopatologia , Hipertensão Arterial Pulmonar/fisiopatologia , Disfunção Ventricular Direita/fisiopatologia , Artérias Brônquicas/patologia , Artérias Brônquicas/fisiopatologia , Circulação Cerebrovascular , Doença da Artéria Coronariana/metabolismo , Endotélio Vascular/fisiopatologia , Humanos , Nefropatias/metabolismo , Doenças Musculares/metabolismo , Hipertensão Arterial Pulmonar/metabolismo , Artéria Pulmonar/patologia , Artéria Pulmonar/fisiopatologia , Músculos Respiratórios/fisiopatologia , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/fisiopatologia , Vasodilatação , Disfunção Ventricular Direita/metabolismo
18.
Chest ; 157(2): 310-322, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31494084

RESUMO

Classically, mitochondria have largely been believed to influence the development of illness by modulating cell metabolism and determining the rate of production of high-energy phosphate compounds (eg, adenosine triphosphate). It is now recognized that this view is simplistic and that mitochondria play key roles in many other processes, including cell signaling, regulating gene expression, modulating cellular calcium levels, and influencing the activation of cell death pathways (eg, caspase activation). Moreover, these multiple mitochondrial functional characteristics are now known to influence the evolution of cellular and organ function in many disease states, including sepsis, ICU-acquired skeletal muscle dysfunction, acute lung injury, acute renal failure, and critical illness-related immune function dysregulation. In addition, diseased mitochondria generate toxic compounds, most notably released mitochondrial DNA, which can act as danger-associated molecular patterns to induce systemic toxicity and damage multiple organs throughout the body. This article reviews these evolving concepts relating mitochondrial function and acute illness. The discussion is organized into four sections: (1) basics of mitochondrial physiology; (2) cellular mechanisms of mitochondrial pathophysiology; (3) critical care disease processes whose initiation and evolution are shaped by mitochondrial pathophysiology; and (4) emerging treatments for mitochondrial dysfunction in critical illness.


Assuntos
Lesão Pulmonar Aguda/metabolismo , Mitocôndrias/metabolismo , Doenças Musculares/metabolismo , Sepse/metabolismo , Lesão Pulmonar Aguda/terapia , Alarminas/metabolismo , Antioxidantes/uso terapêutico , Césio/uso terapêutico , Estado Terminal , DNA Mitocondrial/metabolismo , Humanos , Melatonina/uso terapêutico , Mitocôndrias/imunologia , Mitocôndrias/transplante , Músculo Esquelético , Doenças Musculares/terapia , Biogênese de Organelas , Resveratrol/uso terapêutico , Sepse/imunologia , Sepse/terapia
19.
Toxicol In Vitro ; 62: 104665, 2020 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-31629068

RESUMO

cis-5-Tetradecenoic (cis-5) and myristic (Myr) acids predominantly accumulate in patients affected by very long-chain acyl-CoA dehydrogenase (VLCAD) deficiency. They commonly manifest myopathy with muscular pain and rhabdomyolysis, whose underlying mechanisms are poorly known. Thus, in the present study we investigated the effects of cis-5 and Myr on mitochondrial bioenergetics and Ca2+ homeostasis in rat skeletal muscle. cis-5 and Myr decreased ADP-stimulated (state 3) and CCCP-stimulated (uncoupled) respiration, especially when mitochondria were supported by NADH-linked as compared to FADH2-linked substrates. In contrast, these fatty acids increased resting respiration (state 4). Similar effects were observed in skeletal muscle fibers therefore validating the data obtained with isolated mitochondria. Furthermore, cis-5 and Myr markedly decreased mitochondrial membrane potential and Ca2+ retention capacity that were avoided by cyclosporin A plus ADP and ruthenium red, indicating that cis-5 and Myr induce mitochondrial permeability transition (MPT). Finally, docosanoic acid did not disturb mitochondrial homeostasis, indicating selective effects for Myr and cis-5. Taken together, our findings indicate that major long-chain fatty acids accumulating in VLCAD deficiency behave as metabolic inhibitors, uncouplers of oxidative phosphorylation and MPT inducers. It is presumed that these pathomechanisms contribute to the muscular symptoms and rhabdomyolysis observed in patients affected by VLCAD deficiency.


Assuntos
Acil-CoA Desidrogenase de Cadeia Longa/deficiência , Síndrome Congênita de Insuficiência da Medula Óssea/metabolismo , Erros Inatos do Metabolismo Lipídico/metabolismo , Mitocôndrias/efeitos dos fármacos , Doenças Mitocondriais/metabolismo , Músculo Esquelético/efeitos dos fármacos , Doenças Musculares/metabolismo , Ácidos Mirísticos/toxicidade , Acil-CoA Desidrogenase de Cadeia Longa/metabolismo , Animais , Cálcio/metabolismo , Metabolismo Energético/efeitos dos fármacos , Homeostase/efeitos dos fármacos , Potencial da Membrana Mitocondrial/efeitos dos fármacos , Mitocôndrias/metabolismo , Mitocôndrias/fisiologia , Músculo Esquelético/metabolismo , Consumo de Oxigênio/efeitos dos fármacos , Permeabilidade/efeitos dos fármacos , Ratos Wistar
20.
Mol Biol Rep ; 47(1): 45-53, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31583571

RESUMO

The normalization with proper reference genes is a crucial step to obtain accurate mRNA expression levels in quantitative PCR (qPCR) studies. Therefore, in this study, 10 reference candidate genes were evaluated to determine their stability in normal pectoralis major muscle of broilers and those counterparts affected with White Striping (WS) myopathy at 42 days age. Four different tools were used for ranking the most stable genes: GeNorm, NormFinder, BestKeeper and Comparative Ct (ΔCt), and a general ranking was performed using the RankAggreg tool to select the best reference genes among all tools. From the 10 genes evaluated in the breast muscle of broilers, 8 were amplified. Most of the algorithms/tools indicated the same two genes, RPL30 and RPL5, as the most stable in the broilers breast muscle. In addition, there was agreement among the tools for the least stable genes: MRPS27, GAPDH and RPLP1 in the broilers breast muscle. Therefore, it is interesting to note that even with different tools for evaluating gene expression, there was consensus on the most and least stable genes. These results indicate that the Ribosomal protein L30 (RPL30) and Ribosomal protein L5 (RPL5) can be recommended for accurate normalization in qPCR studies with chicken pectoralis major muscle affected with White Striping and other myopathies.


Assuntos
Galinhas/genética , Perfilação da Expressão Gênica/normas , Genes Essenciais/genética , Doenças Musculares/genética , Músculos Peitorais/metabolismo , Reação em Cadeia da Polimerase em Tempo Real/normas , Animais , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Regulação da Expressão Gênica , Doenças Musculares/metabolismo , Doenças Musculares/veterinária , Doenças das Aves Domésticas/genética , Doenças das Aves Domésticas/metabolismo , Reação em Cadeia da Polimerase em Tempo Real/métodos , Padrões de Referência
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