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1.
Nat Med ; 25(8): 1266-1273, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31285633

RESUMO

The ability to safely control transgene expression with simple synthetic gene switches is critical for effective gene- and cell-based therapies. In the present study, the signaling pathway controlled by human transient receptor potential (TRP) melastatin 8 (hTRPM8), a TRP channel family member1, is harnessed to control transgene expression. Human TRPM8 signaling is stimulated by menthol, an innocuous, natural, cooling compound, or by exposure to a cool environment (15-18 °C). By functionally linking hTRPM8-induced signaling to a synthetic promoter containing elements that bind nuclear factor of activated T cells, a synthetic gene circuit was designed that can be adjusted by exposure to either a cool environment or menthol. It was shown that this gene switch is functional in various cell types and human primary cells, as well as in mice implanted with engineered cells. In response to transdermal delivery of menthol, microencapsulated cell implants harboring this gene circuit, coupled to expression of either of two therapeutic proteins, insulin or a modified, activin type IIB, receptor ligand trap protein (mActRIIBECD-hFc), could alleviate hyperglycemia in alloxan-treated mice (a model of type 1 diabetes) or reverse muscle atrophy in dexamethasone-treated mice (a model of muscle wasting), respectively. This fully human-derived orthogonal transgene switch should be amenable to a wide range of clinical applications.


Assuntos
Receptores de Activinas Tipo II/sangue , Insulina/biossíntese , Canais de Cátion TRPM/fisiologia , Transgenes , Receptores de Activinas Tipo II/genética , Receptores de Activinas Tipo II/uso terapêutico , Fosfatase Alcalina/genética , Animais , Temperatura Baixa , Diabetes Mellitus Tipo 1/tratamento farmacológico , Sistemas de Liberação de Medicamentos , Feminino , Regulação da Expressão Gênica , Células HEK293 , Humanos , Insulina/genética , Insulina/uso terapêutico , Mentol/farmacologia , Camundongos , Camundongos Endogâmicos C57BL , Distrofias Musculares/tratamento farmacológico , Transdução de Sinais/efeitos dos fármacos
2.
Sci Rep ; 8(1): 16302, 2018 11 02.
Artigo em Inglês | MEDLINE | ID: mdl-30389963

RESUMO

Congenital muscular dystrophy with laminin α2 chain-deficiency (LAMA2-CMD) is a severe muscle disorder with complex underlying pathogenesis. We have previously employed profiling techniques to elucidate molecular patterns and demonstrated significant metabolic impairment in skeletal muscle from LAMA2-CMD patients and mouse models. Thus, we hypothesize that skeletal muscle metabolism may be a promising pharmacological target to improve muscle function in LAMA2-CMD. Here, we have investigated whether the multifunctional medication metformin could be used to reduce disease in the dy2J/dy2J mouse model of LAMA2-CMD. First, we show gender disparity for several pathological hallmarks of LAMA2-CMD. Second, we demonstrate that metformin treatment significantly increases weight gain and energy efficiency, enhances muscle function and improves skeletal muscle histology in female dy2J/dy2J mice (and to a lesser extent in dy2J/dy2J males). Thus, our current data suggest that metformin may be a potential future supportive treatment that improves many of the pathological characteristics of LAMA2-CMD.


Assuntos
Disparidades nos Níveis de Saúde , Lamina Tipo A/deficiência , Metformina/administração & dosagem , Músculo Esquelético/efeitos dos fármacos , Distrofias Musculares/tratamento farmacológico , Distrofia Muscular Animal/tratamento farmacológico , Administração Oral , Animais , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Lamina Tipo A/genética , Laminina/genética , Masculino , Camundongos , Músculo Esquelético/patologia , Distrofias Musculares/genética , Distrofias Musculares/patologia , Distrofia Muscular Animal/genética , Distrofia Muscular Animal/patologia , Fatores Sexuais , Resultado do Tratamento
3.
Skelet Muscle ; 8(1): 34, 2018 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-30368252

RESUMO

BACKGROUND: Myostatin antagonists are being developed as therapies for Duchenne muscular dystrophy due to their strong hypertrophic effects on skeletal muscle. Engineered follistatin has the potential to combine the hypertrophy of myostatin antagonism with the anti-inflammatory and anti-fibrotic effects of activin A antagonism. METHODS: Engineered follistatin was administered to C57BL/6 mice for 4 weeks, and muscle mass and myofiber size was measured. In the mdx model, engineered follistatin was dosed for 12 weeks in two studies comparing to an Fc fusion of the activin IIB receptor or an anti-myostatin antibody. Functional measurements of grip strength and tetanic force were combined with tissue analysis for markers of necrosis, inflammation, and fibrosis to evaluate improvement in dystrophic pathology. RESULTS: In wild-type and mdx mice, dose-dependent increases in muscle mass and quadriceps myofiber size were observed for engineered follistatin. In mdx, increases in grip strength and tetanic force were combined with improvements in muscle markers for necrosis, inflammation, and fibrosis. Improvements in dystrophic pathology were greater for engineered follistatin than the anti-myostatin antibody. CONCLUSIONS: Engineered follistatin generated hypertrophy and anti-fibrotic effects in the mdx model.


Assuntos
Ativinas/antagonistas & inibidores , Folistatina/uso terapêutico , Distrofias Musculares/tratamento farmacológico , Miostatina/antagonistas & inibidores , Animais , Folistatina/administração & dosagem , Força da Mão , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Contração Muscular , Proteínas Recombinantes/administração & dosagem , Proteínas Recombinantes/uso terapêutico
4.
JCI Insight ; 3(18)2018 09 20.
Artigo em Inglês | MEDLINE | ID: mdl-30232282

RESUMO

Zebrafish are a powerful tool for studying muscle function owing to their high numbers of offspring, low maintenance costs, evolutionarily conserved muscle functions, and the ability to rapidly take up small molecular compounds during early larval stages. Fukutin-related protein (FKRP) is a putative protein glycosyltransferase that functions in the Golgi apparatus to modify sugar chain molecules of newly translated proteins. Patients with mutations in the FKRP gene can have a wide spectrum of clinical symptoms with varying muscle, eye, and brain pathologies depending on the location of the mutation in the FKRP protein. Patients with a common L276I FKRP mutation have mild adult-onset muscle degeneration known as limb-girdle muscular dystrophy 2I (LGMD2I), whereas patients with more C-terminal pathogenic mutations develop the severe Walker-Warburg syndrome (WWS)/muscle-eye-brain (MEB) disease. We generated fkrp-mutant zebrafish that phenocopy WWS/MEB pathologies including severe muscle breakdowns, head malformations, and early lethality. We have also generated a milder LGMD2I-model zebrafish via overexpression of a heat shock-inducible human FKRP (L276I) transgene that shows milder muscle pathology. Screening of an FDA-approved drug compound library in the LGMD2I zebrafish revealed a strong propensity towards steroids, antibacterials, and calcium regulators in ameliorating FKRP-dependent pathologies. Together, these studies demonstrate the utility of the zebrafish to both study human-specific FKRP mutations and perform compound library screenings for corrective drug compounds to treat muscular dystrophies.


Assuntos
Glicosiltransferases/genética , Glicosiltransferases/metabolismo , Distrofia Muscular do Cíngulo dos Membros/tratamento farmacológico , Distrofia Muscular do Cíngulo dos Membros/fisiopatologia , Distrofias Musculares/tratamento farmacológico , Distrofias Musculares/fisiopatologia , Proteínas de Peixe-Zebra/genética , Proteínas de Peixe-Zebra/metabolismo , Animais , Animais Geneticamente Modificados , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Técnicas de Inativação de Genes , Humanos , Locomoção , Movimento , Músculo Esquelético/fisiopatologia , Distrofias Musculares/genética , Distrofia Muscular do Cíngulo dos Membros/genética , Mutação , Pentosiltransferases , Fenótipo , Proteínas , Transcriptoma , Síndrome de Walker-Warburg , Peixe-Zebra
5.
Mol Ther ; 26(9): 2231-2242, 2018 09 05.
Artigo em Inglês | MEDLINE | ID: mdl-30166241

RESUMO

Mutations of the DYSF gene leading to reduced dysferlin protein level causes limb girdle muscular dystrophy type 2B (LGMD2B). Dysferlin facilitates sarcolemmal membrane repair in healthy myofibers, thus its deficit compromises myofiber repair and leads to chronic muscle inflammation. An experimental therapeutic approach for LGMD2B is to protect damage or improve repair of myofiber sarcolemma. Here, we compared the effects of prednisolone and vamorolone (a dissociative steroid; VBP15) on dysferlin-deficient myofiber repair. Vamorolone, but not prednisolone, stabilized dysferlin-deficient muscle cell membrane and improved repair of dysferlin-deficient mouse (B6A/J) myofibers injured by focal sarcolemmal damage, eccentric contraction-induced injury or injury due to spontaneous in vivo activity. Vamorolone decreased sarcolemmal lipid mobility, increased muscle strength, and decreased late-stage myofiber loss due to adipogenic infiltration. In contrast, the conventional glucocorticoid prednisolone failed to stabilize dysferlin deficient muscle cell membrane or improve repair of dysferlinopathic patient myoblasts and mouse myofibers. Instead, prednisolone treatment increased muscle weakness and myofiber atrophy in B6A/J mice-findings that correlate with reports of prednisolone worsening symptoms of LGMD2B patients. Our findings showing improved cellular and pre-clinical efficacy of vamorolone compared to prednisolone and better safety profile of vamorolone indicates the suitability of vamorolone for clinical trials in LGMD2B.


Assuntos
Disferlina/deficiência , Distrofias Musculares/tratamento farmacológico , Esteroides/uso terapêutico , Adolescente , Animais , Células Cultivadas , Disferlina/metabolismo , Humanos , Masculino , Camundongos , Mioblastos/efeitos dos fármacos , Mioblastos/metabolismo , Prednisolona/uso terapêutico , Pregnadienodiois/uso terapêutico
6.
Nat Commun ; 9(1): 3448, 2018 08 27.
Artigo em Inglês | MEDLINE | ID: mdl-30150693

RESUMO

O-mannosylated α-dystroglycan (α-DG) serves as receptors for cell-cell and cell-extracellular matrix adhesion and signaling. Hypoglycosylation of α-DG is involved in cancer progression and underlies dystroglycanopathy with aberrant neuronal development. Here we report that ribitol, a pentose alcohol with previously unknown function in mammalian cells, partially restores functional O-mannosylation of α-DG (F-α-DG) in the dystroglycanopathy model containing a P448L mutation in fukutin-related protein (FKRP) gene, which is clinically associated with severe congenital muscular dystrophy. Oral administration of ribitol increases levels of ribitol-5-phosphate and CDP-ribitol and restores therapeutic levels of F-α-DG in skeletal and cardiac muscles. Furthermore, ribitol, given before and after the onset of disease phenotype, reduces skeletal muscle pathology, significantly decreases cardiac fibrosis and improves skeletal and respiratory functions in the FKRP mutant mice. Ribitol treatment presents a new class, low risk, and easy to administer experimental therapy to restore F-α-DG in FKRP-related muscular dystrophy.


Assuntos
Distroglicanas/metabolismo , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/metabolismo , Distrofias Musculares/tratamento farmacológico , Distrofias Musculares/metabolismo , Proteínas/metabolismo , Ribitol/uso terapêutico , Administração Oral , Animais , Western Blotting , Linhagem Celular , Feminino , Glicosilação/efeitos dos fármacos , Imuno-Histoquímica , Camundongos , Miocárdio/metabolismo , Pentosefosfatos/metabolismo , Pletismografia , Proteínas/genética , Transferases
7.
Dis Markers ; 2018: 6484610, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30018675

RESUMO

Objective: To investigate the ratios of creatine kinase (CK) to aminotransferases as biomarkers of acute liver injury in dystrophinopathy. Methods: C57 and mdx (dystrophic) mice were treated with a hepatotoxic reagent D-galactosamine (D-GalN). The degrees of liver and muscle injury were assessed using histological examinations. To examine whether serum CK-adjusted aminotransferase levels could indicate liver status in dystrophic mice, the CK/alanine aminotransferase (ALT) and CK/aspartate aminotransferase (AST) ratios were analyzed. Furthermore, we enrolled 658 male patients with dystrophinopathy and 378 male patients without muscle and liver injury as control, whose serum ALT, AST, and CK levels were examined. Results: Animal experiments indicated that D-GalN treatment could induce acute liver injury but not muscle injury. Additionally, D-GalN decreased the CK/ALT and CK/AST ratios in both C57 mice and mdx mice (P < 0.001). However, there was an overlap of the CK/AST ratio between dystrophic mice with and without acute liver injury. In patients with dystrophinopathy, CK-adjusted ALT diminished the variability associated with age, genotype, clinical phenotype, and motor function (P > 0.05). Conclusions: CK/ALT is a potential biomarker for the differential evaluation of acute liver injury in dystrophic mice, which highlights the value to further evaluate the practice of CK/ALT in dystrophinopathy patients.


Assuntos
Alanina Transaminase/sangue , Doença Hepática Induzida por Substâncias e Drogas/sangue , Creatina Quinase/sangue , Distrofias Musculares/complicações , Adolescente , Animais , Biomarcadores/sangue , Doença Hepática Induzida por Substâncias e Drogas/etiologia , Criança , Galactosamina/efeitos adversos , Galactosamina/uso terapêutico , Humanos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Distrofias Musculares/tratamento farmacológico
10.
J Biochem ; 163(5): 359-369, 2018 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-29394359

RESUMO

Glycosylation is a crucial posttranslational modification that is involved in numerous biological events. Therefore, abnormal glycosylation can impair the functions of glycoproteins or glycolipids and is occasionally associated with cell dysfunction and human diseases. For example, aberrant glycosylation of dystroglycan (DG), a cellular receptor for matrix and synaptic proteins, is associated with muscular dystrophy and lissencephaly. DG sugar chains are required for high-affinity binding to ligand proteins, and thus disruption of DG-ligand linkages underlies disease conditions. Although their biological significance is well recognized, the sugar-chain structure of DG and its modification enzymes have long remained incompletely elucidated. However, recent seminal studies have finally revealed a highly regulated mechanism for DG glycosylation and have discovered a posttranslational unit, ribitol-phosphate, that was not previously known to be used in mammals. This review article introduces the structure, modification enzymes and functions of the sugar chains of DG, and then discusses their relationship to human diseases and therapeutic strategies: .


Assuntos
Distroglicanas/metabolismo , Glicosiltransferases/metabolismo , Distrofias Musculares/metabolismo , Pentosefosfatos/metabolismo , Animais , Distroglicanas/biossíntese , Distroglicanas/química , Glicosilação , Humanos , Distrofias Musculares/tratamento farmacológico , Pentosefosfatos/química , Conformação Proteica
11.
Trends Cardiovasc Med ; 28(5): 330-337, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29292032

RESUMO

Muscular dystrophy (MD) connotes a heterogeneous group of inherited disordersaffecting skeletal and cardiac muscle. Inseveral forms of MD, the cardiac disease may be the predominant manifestationof the underlying genetic myopathy. The cardiacinvolvement is due to progressive interstitial fibrosis and fatty replacement inboth the atria and ventricles, which may lead to cardiomyopathy, conductiondefects and tachyarrhythmias. Angiotensin-convertingenzyme inhibitors (ACE-Is) modulate the production of angiotensin II and limitthe amount of fibrosis in the myocardium, reducing mortality andhospitalization in cardiac patients. The aim of present review is to describethe antifibrotic proprieties of ACE inhibitor therapy and to summarize thecurrent body of scientific literature relating to the use of ACE-Is for theprevention and treatment of cardiomyopathy in patients with musculardystrophies.


Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Cardiomiopatias/prevenção & controle , Distrofias Musculares/tratamento farmacológico , Miocárdio/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Animais , Cardiomiopatias/diagnóstico , Cardiomiopatias/etiologia , Cardiomiopatias/metabolismo , Modelos Animais de Doenças , Progressão da Doença , Fibrose , Humanos , Distrofias Musculares/complicações , Distrofias Musculares/diagnóstico , Distrofias Musculares/metabolismo , Miocárdio/patologia , Resultado do Tratamento
12.
Skelet Muscle ; 7(1): 23, 2017 10 27.
Artigo em Inglês | MEDLINE | ID: mdl-29078808

RESUMO

BACKGROUND: Chronic increases in the levels of the inflammatory cytokine interleukin-6 (IL-6) in serum and skeletal muscle are thought to contribute to the progression of muscular dystrophy. Dystrophin/utrophin double-knockout (dKO) mice develop a more severe and progressive muscular dystrophy than the mdx mice, the most common murine model of Duchenne muscular dystrophy (DMD). In particular, dKO mice have smaller body sizes and muscle diameters, and develop progressive kyphosis and fibrosis in skeletal and cardiac muscles. As mdx mice and DMD patients, we found that IL-6 levels in the skeletal muscle were significantly increased in dKO mice. Thus, in this study, we aimed to analyze the effects of IL-6 receptor (IL-6R) blockade on the muscle pathology of dKO mice. METHODS: Male dKO mice were administered an initial injection (200 mg/kg intraperitoneally (i.p.)) of either the anti-IL-6R antibody MR16-1 or an isotype-matched control rat IgG at the age of 14 days, and were then given weekly injections (25 mg/kg i.p.) until 90 days of age. RESULTS: Treatment of dKO mice with the MR16-1 antibody successfully inhibited the IL-6 pathway in the skeletal muscle and resulted in a significant reduction in the expression levels of phosphorylated signal transducer and activator of transcription 3 in the skeletal muscle. Pathologically, a significant increase in the area of embryonic myosin heavy chain-positive myofibers and muscle diameter, and reduced fibrosis in the quadriceps muscle were observed. These results demonstrated the therapeutic effects of IL-6R blockade on promoting muscle regeneration. Consistently, serum creatine kinase levels were decreased. Despite these improvements observed in the limb muscles, degeneration of the diaphragm and cardiac muscles was not ameliorated by the treatment of mice with the MR16-1 antibody. CONCLUSION: As no adverse effects of treatment with the MR16-1 antibody were observed, our results indicate that the anti-IL-6R antibody is a potential therapy for muscular dystrophy particularly for promoting skeletal muscle regeneration.


Assuntos
Anticorpos/administração & dosagem , Músculo Esquelético/efeitos dos fármacos , Distrofias Musculares/tratamento farmacológico , Receptores de Interleucina-6/imunologia , Regeneração/efeitos dos fármacos , Animais , Creatina Quinase/sangue , Modelos Animais de Doenças , Distrofina/genética , Fibrose/complicações , Inflamação/complicações , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofias Musculares/complicações , Distrofias Musculares/imunologia , Receptores de Interleucina-6/antagonistas & inibidores , Células Satélites de Músculo Esquelético/efeitos dos fármacos , Transdução de Sinais/efeitos dos fármacos , Utrofina/genética
13.
Acta Myol ; 36(1): 19-24, 2017 03.
Artigo em Inglês | MEDLINE | ID: mdl-28690390

RESUMO

This paper describes the pharmacological therapies and rehabilitative interventions received by 502 patients with Muscular Dystrophies, evaluated in relation to patient's socio-demographic and clinical variables, and geographical areas. Data were collected by the MD-Socio-Demographic and Clinical Schedule (MD-SC-CS) and by the Family Problems Questionnaire (FPQ). The most part of the enrolled patients were in drug treatment. The number of the medications increased in relation to patient's age, disability degree and duration of illness and was higher among patients with Duchenne Muscular Dystrophy (DMD) compared with Becker (BMD) or Limb-Girdle Muscular Dystrophies (LGMD). Steroids (deflazacort or prednisone) were the drug most frequently used, followed by cardiologic and bone metabolism drugs. In general, patients using steroids were younger and had a shorter duration of illness; patients using cardiac drugs and dietary supplements were older and had a longer duration of illness. Rehabilitative interventions were provided to about 70% (351/502) of patients, mainly DMD. Of these, physiotherapy was the more frequent treatment (96.6%) and was prevalently performed in rehabilitative centres (about 70% of patients) and at home in only 30%. Hydrokinetic-therapy was practiced by 6.8% of patients. Respiratory rehabilitation was provided to 47.0% of patients (165/351) and assisted mechanical ventilaventilation to 13.1% (46). The amount of rehabilitative interventions increased in relation to the patient's age, level of disability and duration of illness. Compared to Central and Northern Italy, in Southern Italy there was a higher attention to cardiological impairment as shown by a higher number of patients receiving heart drugs. No statistically significant differences concerning the possibility to have access to rehabilitative interventions were noted among the three geographical areas. However, patient living in Southern Italy tend to receive rehabilitation more often at home.


Assuntos
Glucocorticoides/uso terapêutico , Distrofias Musculares/tratamento farmacológico , Distrofias Musculares/reabilitação , Modalidades de Fisioterapia , Adolescente , Fatores Etários , Conservadores da Densidade Óssea/uso terapêutico , Exercícios Respiratórios , Cardiotônicos/uso terapêutico , Criança , Terapia Combinada , Suplementos Nutricionais , Avaliação da Deficiência , Feminino , Pesquisas sobre Serviços de Saúde , Humanos , Itália , Masculino , Prednisona/uso terapêutico , Pregnenodionas/uso terapêutico , Respiração Artificial , Fatores de Tempo
14.
Clin Calcium ; 27(6): 789-794, 2017.
Artigo em Japonês | MEDLINE | ID: mdl-28536315

RESUMO

Adult skeletal muscle has its own stem cell population known as satellite cells. After muscle injury, quiescent satellite cells are activated and then proliferate and differentiate into mature skeletal muscle to ensure that muscle function is recovered. In our screen for myocyte differentiation-promoting factors, we noted markedly elevated expression of granulocyte-colony stimulating factor receptor(G-CSFR, encoded by csf3r)in the skeletal muscle developing area. Furthermore, G-CSFR was transiently expressed in regenerating myocytes of adult injured skeletal muscle, and extrinsic G-CSF supported short-term and long-term muscle regeneration in mouse model of skeletal muscle injury.


Assuntos
Músculo Esquelético/citologia , Músculo Esquelético/fisiologia , Regeneração , Células-Tronco/citologia , Animais , Fator Estimulador de Colônias de Granulócitos/metabolismo , Fator Estimulador de Colônias de Granulócitos/uso terapêutico , Humanos , Distrofias Musculares/tratamento farmacológico , Distrofias Musculares/fisiopatologia , Células-Tronco/metabolismo
17.
Curr Med Chem ; 24(3): 312-330, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27897115

RESUMO

BACKGROUND: Muscular dystrophies are inherited disorders characterized by progressive skeletal muscle degeneration without curative therapy. The specific defective protein in each type of muscular dystrophy has been associated with different deleterious factors that contribute to the progression of the disease. Among these factors, the impairment of calcium homeostasis, the ubiquitin-proteasome dysfunction, and the oxidative damage of cellular macromolecules seem to be of central importance. Can these different cellular dysfunctions be linked by a common pathogenic mechanism susceptible to therapy? A cellular cysteine network (CYSTEINET) has been proposed previously, as a matrix of interconnected sensitive cysteine-containing proteins (SCCPs) that in addition to reactive species and the cysteine/glutathione cycles can regulate metabolic, redox, and survival cellular pathways by a complex biochemical network of proteins with different functions, but sharing the same regulatory thiol group. OBJECTIVE: Since there are many sensitive cysteine-containing proteins including cysteinedependent enzymes susceptible to redox modifications at cysteine residues that may contribute to muscular degeneration, the aim of this review is to propose that cysteinet dysregulation may explain oxidative damage, calcium disturbances and ubiquitin-proteasome dysfunctions associated with muscular dystrophies. CONCLUSION: The present review proposes that cysteinet dysregulation in muscular dystrophies may represent a common pathogenic network contributing, in association with the specific protein dysfunction, to muscular degeneration. In this context, N-acetylcysteine may have an important role in the restoration of the proposed cysteinet dysregulation associated with these heterogeneous types of diseases.


Assuntos
Cisteína/metabolismo , Distrofias Musculares/metabolismo , Distrofias Musculares/terapia , Acetilcisteína/farmacocinética , Acetilcisteína/farmacologia , Acetilcisteína/uso terapêutico , Animais , Humanos , Distrofias Musculares/tratamento farmacológico
18.
Am J Physiol Cell Physiol ; 312(2): C155-C168, 2017 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-27881412

RESUMO

Angiotensin-converting enzyme inhibitors (ACEi) and mineralocorticoid receptor (MR) antagonists are FDA-approved drugs that inhibit the renin-angiotensin-aldosterone system (RAAS) and are used to treat heart failure. Combined treatment with the ACEi lisinopril and the nonspecific MR antagonist spironolactone surprisingly improves skeletal muscle, in addition to heart function and pathology in a Duchenne muscular dystrophy (DMD) mouse model. We recently demonstrated that MR is present in all limb and respiratory muscles and functions as a steroid hormone receptor in differentiated normal human skeletal muscle fibers. The goals of the current study were to begin to define cellular and molecular mechanisms mediating the skeletal muscle efficacy of RAAS inhibitor treatment. We also compared molecular changes resulting from RAAS inhibition with those resulting from the current DMD standard-of-care glucocorticoid treatment. Direct assessment of muscle membrane integrity demonstrated improvement in dystrophic mice treated with lisinopril and spironolactone compared with untreated mice. Short-term treatments of dystrophic mice with specific and nonspecific MR antagonists combined with lisinopril led to overlapping gene-expression profiles with beneficial regulation of metabolic processes and decreased inflammatory gene expression. Glucocorticoids increased apoptotic, proteolytic, and chemokine gene expression that was not changed by RAAS inhibitors in dystrophic mice. Microarray data identified potential genes that may underlie RAAS inhibitor treatment efficacy and the side effects of glucocorticoids. Direct effects of RAAS inhibitors on membrane integrity also contribute to improved pathology of dystrophic muscles. Together, these data will inform clinical development of MR antagonists for treating skeletal muscles in DMD.


Assuntos
Membrana Celular/efeitos dos fármacos , Antagonistas de Receptores de Mineralocorticoides/administração & dosagem , Proteínas Musculares/metabolismo , Distrofias Musculares/tratamento farmacológico , Distrofias Musculares/metabolismo , Sistema Renina-Angiotensina/efeitos dos fármacos , Inibidores da Enzima Conversora de Angiotensina/administração & dosagem , Animais , Membrana Celular/patologia , Relação Dose-Resposta a Droga , Regulação da Expressão Gênica/efeitos dos fármacos , Lisinopril/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Distrofias Musculares/patologia , Espironolactona/administração & dosagem , Resultado do Tratamento
19.
Cytokine Growth Factor Rev ; 33: 65-72, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27769579

RESUMO

Choline, a hydrophilic cation, has versatile physiological roles throughout the body, including cholinergic neurotransmission, memory consolidation and membrane biosynthesis and metabolism. Choline kinases possess enzyme activity that catalyses the conversion of choline to phosphocholine, which is further converted to cytidine diphosphate-coline (CDP-choline) in the biosynthesis of phosphatidylcholine (PC). PC is a major constituent of the phospholipid bilayer which constitutes the eukaryotic cell membrane, and regulates cell signal transduction. Choline Kinase consists of three isoforms, CHKα1, CHKα2 and CHKß, encoded by two separate genes (CHKA(Human)/Chka(Mouse) and CHKB(Human)/Chkb(Mouse)). Both isoforms have similar structures and enzyme activity, but display some distinct molecular structural domains and differential tissue expression patterns. Whilst Choline Kinase was discovered in early 1950, its pivotal role in the development of muscular dystrophy, bone deformities, and cancer has only recently been identified. CHKα has been proposed as a cancer biomarker and its inhibition as an anti-cancer therapy. In contrast, restoration of CHKß deficiency through CDP-choline supplements like citicoline may be beneficial for the treatment of muscular dystrophy, bone metabolic diseases, and cognitive conditions. The molecular structure and expression pattern of Choline Kinase, the differential roles of Choline Kinase isoforms and their potential as novel therapeutic targets for muscular dystrophy, bone deformities, cognitive conditions and cancer are discussed.


Assuntos
Colina Quinase/química , Colina Quinase/metabolismo , Sistema Musculoesquelético/enzimologia , Neoplasias/enzimologia , Animais , Biomarcadores Tumorais , Colina Quinase/deficiência , Colina Quinase/genética , Humanos , Doenças Metabólicas/tratamento farmacológico , Camundongos , Estrutura Molecular , Distrofias Musculares/tratamento farmacológico , Sistema Musculoesquelético/fisiopatologia , Neoplasias/fisiopatologia
20.
Clin Transl Sci ; 9(6): 302-310, 2016 12.
Artigo em Inglês | MEDLINE | ID: mdl-27700008

RESUMO

Suppression of the myostatin (GDF-8) pathway has emerged as an important therapeutic paradigm for muscle-wasting disorders. In this study, we conducted a translational pharmacokinetic/pharmacodynamic (PK/PD) analysis of MYO-029, an anti-myostatin monoclonal antibody, using PK data in mice, rats, monkeys, humans, mouse tissue distribution data with 125 I-labeled MYO-029, muscle weight increase in SCID mice, and muscle circumference changes in monkeys. This analysis revealed significant in vivo potency shift between mice and monkeys (72 nM vs. 1.3 µM for 50% effect on quadriceps). Estimated central clearance of MYO-029 (0.38 mL/h/kg) in humans was greater than twofold higher than typical IgG mAbs. Peak and trough steady-state exposures of MYO-029 in patients at biweekly intravenous doses of 10 mg/kg MYO-029 are predicted to achieve only 50% and 10% of the maximum effect seen in monkeys, respectively. These retrospective analyses results suggest that the MYO-029 exposures in this trial had a low probability of producing robust efficacy.


Assuntos
Anticorpos/farmacologia , Anticorpos/uso terapêutico , Distrofias Musculares/tratamento farmacológico , Pesquisa Médica Translacional , Animais , Anticorpos/sangue , Área Sob a Curva , Relação Dose-Resposta a Droga , Feminino , Macaca fascicularis , Masculino , Camundongos Endogâmicos C57BL , Camundongos SCID , Desenvolvimento Muscular/efeitos dos fármacos , Distrofias Musculares/patologia , Ratos Sprague-Dawley , Distribuição Tecidual/efeitos dos fármacos
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