RESUMO
Peripartum cardiomyopathy (PPCM) is an often fatal disease that affects pregnant women who are near delivery, and it occurs more frequently in women with pre-eclampsia and/or multiple gestation. The aetiology of PPCM, and why it is associated with pre-eclampsia, remain unknown. Here we show that PPCM is associated with a systemic angiogenic imbalance, accentuated by pre-eclampsia. Mice that lack cardiac PGC-1α, a powerful regulator of angiogenesis, develop profound PPCM. Importantly, the PPCM is entirely rescued by pro-angiogenic therapies. In humans, the placenta in late gestation secretes VEGF inhibitors like soluble FLT1 (sFLT1), and this is accentuated by multiple gestation and pre-eclampsia. This anti-angiogenic environment is accompanied by subclinical cardiac dysfunction, the extent of which correlates with circulating levels of sFLT1. Exogenous sFLT1 alone caused diastolic dysfunction in wild-type mice, and profound systolic dysfunction in mice lacking cardiac PGC-1α. Finally, plasma samples from women with PPCM contained abnormally high levels of sFLT1. These data indicate that PPCM is mainly a vascular disease, caused by excess anti-angiogenic signalling in the peripartum period. The data also explain how late pregnancy poses a threat to cardiac homeostasis, and why pre-eclampsia and multiple gestation are important risk factors for the development of PPCM.
Assuntos
Cardiomiopatias/etiologia , Cardiomiopatias/fisiopatologia , Neovascularização Patológica/complicações , Neovascularização Patológica/fisiopatologia , Complicações Cardiovasculares na Gravidez/etiologia , Complicações Cardiovasculares na Gravidez/fisiopatologia , Animais , Bromocriptina/farmacologia , Bromocriptina/uso terapêutico , Cardiomiopatias/sangue , Cardiomiopatias/tratamento farmacológico , Modelos Animais de Doenças , Feminino , Coração/efeitos dos fármacos , Coração/fisiopatologia , Humanos , Estimativa de Kaplan-Meier , Masculino , Camundongos , Camundongos Knockout , Miócitos Cardíacos/efeitos dos fármacos , Miócitos Cardíacos/metabolismo , Neovascularização Patológica/tratamento farmacológico , Neovascularização Fisiológica/efeitos dos fármacos , Neovascularização Fisiológica/fisiologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Pré-Eclâmpsia/fisiopatologia , Gravidez , Complicações Cardiovasculares na Gravidez/sangue , Complicações Cardiovasculares na Gravidez/tratamento farmacológico , Transativadores/deficiência , Transativadores/genética , Transativadores/metabolismo , Fatores de Transcrição , Fator A de Crescimento do Endotélio Vascular/farmacologia , Fator A de Crescimento do Endotélio Vascular/uso terapêutico , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/farmacologiaRESUMO
BACKGROUND: Aseptic glenoid baseplate loosening (AGBL) is a catastrophic complication after reverse total shoulder arthroplasty (RTSA). Our goals were to determine the incidence of AGBL in patients who underwent RTSA and identify risk factors for AGBL after RTSA. METHODS: We analyzed 202 shoulders that underwent primary or revision RTSA using 1 implant system and evaluated baseplate loosening at a minimum 2-year follow-up. The associations between AGBL and the following variables were investigated: patient age, sex, primary vs. revision RTSA, scapular notching, use of bone graft, and type of baseplate screw fixation. RESULTS: AGBL occurred in 6 shoulders (3.0%). The incidence of AGBL after revision RTSA (10%) was significantly higher than that after primary RTSA (1.2%; P = .014). There were significant associations between AGBL and the use of bone graft and the use of nonlocking screws. Scapular notching, glenosphere center-of-rotation offset, patient age, and sex were not associated with AGBL. Multiple logistic regression analysis showed that the use of all peripheral nonlocking 3.5-mm screws (odds ratio, 10.6; 95% confidence interval, 1.1- 39) and the use of bone graft (odds ratio, 7.5; 95% confidence interval, 1.9-30) were independent risk factors for AGBL. CONCLUSIONS: The rate of baseplate failure after primary RTSA is low (1.2%) but is significantly higher after revision RTSA (10%). Major risk factors for baseplate failure are the use of all 3.5-mm nonlocking screws for peripheral baseplate fixation and the use of a bone graft to address deficiencies in bony support beneath the baseplate.
Assuntos
Artroplastia do Ombro/efeitos adversos , Falha de Prótese/etiologia , Prótese de Ombro/efeitos adversos , Adulto , Idoso , Idoso de 80 Anos ou mais , Artroplastia do Ombro/instrumentação , Parafusos Ósseos/efeitos adversos , Transplante Ósseo/efeitos adversos , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Reoperação , Fatores de Risco , Resultado do Tratamento , Adulto JovemRESUMO
RATIONALE: Mechanisms of angiogenesis in skeletal muscle remain poorly understood. Efforts to induce physiological angiogenesis hold promise for the treatment of diabetic microvascular disease and peripheral artery disease but are hindered by the complexity of physiological angiogenesis and by the poor angiogenic response of aged and patients with diabetes mellitus. To date, the best therapy for diabetic vascular disease remains exercise, often a challenging option for patients with leg pain. Peroxisome proliferation activator receptor-γ coactivator-1α (PGC-1α), a powerful regulator of metabolism, mediates exercise-induced angiogenesis in skeletal muscle. OBJECTIVE: To test whether, and how, PGC-1α can induce functional angiogenesis in adult skeletal muscle. METHODS AND RESULTS: Here, we show that muscle PGC-1α robustly induces functional angiogenesis in adult, aged, and diabetic mice. The process involves the orchestration of numerous cell types and leads to patent, nonleaky, properly organized, and functional nascent vessels. These findings contrast sharply with the disorganized vasculature elicited by induction of vascular endothelial growth factor alone. Bioinformatic analyses revealed that PGC-1α induces the secretion of secreted phosphoprotein 1 and the recruitment of macrophages. Secreted phosphoprotein 1 stimulates macrophages to secrete monocyte chemoattractant protein-1, which then activates adjacent endothelial cells, pericytes, and smooth muscle cells. In contrast, induction of PGC-1α in secreted phosphoprotein 1(-/-) mice leads to immature capillarization and blunted arteriolarization. Finally, adenoviral delivery of PGC-1α into skeletal muscle of either young or old and diabetic mice improved the recovery of blood flow in the murine hindlimb ischemia model of peripheral artery disease. CONCLUSIONS: PGC-1α drives functional angiogenesis in skeletal muscle and likely recapitulates the complex physiological angiogenesis elicited by exercise.
Assuntos
Ativação de Macrófagos , Macrófagos/metabolismo , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Neovascularização Fisiológica , Osteopontina/metabolismo , Fatores de Transcrição/metabolismo , Adenoviridae/genética , Animais , Comunicação Celular , Linhagem Celular , Movimento Celular , Quimiocina CCL2/metabolismo , Diabetes Mellitus/genética , Diabetes Mellitus/metabolismo , Diabetes Mellitus/fisiopatologia , Diabetes Mellitus/terapia , Modelos Animais de Doenças , Terapia Genética/métodos , Vetores Genéticos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Isquemia/genética , Isquemia/metabolismo , Isquemia/fisiopatologia , Isquemia/terapia , Camundongos , Camundongos da Linhagem 129 , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos Transgênicos , Fibras Musculares Esqueléticas/metabolismo , Osteopontina/deficiência , Osteopontina/genética , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fluxo Sanguíneo Regional , Transdução de Sinais , Fatores de Tempo , Fatores de Transcrição/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/genética , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismoRESUMO
Background: A common practice in hip arthroscopic surgery is the utilization of capsular traction sutures that can be incorporated into the capsular repair site at the end of the procedure, potentially seeding the hip joint with colonized suture material. Purpose: To investigate the rate of the microbial colonization of capsular traction sutures used during hip arthroscopic surgery and to identify patient-associated risk factors for this microbial colonization. Study Design: Cross-sectional study; Level of evidence, 3. Methods: A total of 50 consecutive patients who underwent hip arthroscopic surgery with a single surgeon were enrolled. There were 4 braided nonabsorbable sutures utilized for capsular traction during each hip arthroscopic procedure. These 4 traction sutures and 1 control suture were submitted for aerobic and nonaerobic cultures. Cultures were held for 21 days. Demographic information was collected, such as age, sex, and body mass index. All variables underwent bivariate analysis, and variables with a P value <.1 underwent further analysis in a multivariate logistic regression model. Results: One of 200 experimental traction sutures and 1 of 50 control sutures had a positive culture. Proteus mirabilis and Citrobacter koseri were isolated in both these positive experimental and control cultures from the same patient. Age and traction time were not significantly associated with positive cultures. The rate of microbial colonization was 0.5%. Conclusion: The rate of the microbial colonization of capsular traction sutures used in hip arthroscopic surgery was low, and no patient-associated risk factors were identified for microbial colonization. Capsular traction sutures used in hip arthroscopic surgery were not a significant potential source of microbial contamination. Based on these results, capsular traction sutures can be incorporated in capsular closure with a low risk of seeding the hip joint with microbial contaminants.
RESUMO
Aerobic metabolism requires oxygen and carbon sources brought to tissues via the vasculature. Metabolically active tissues such as skeletal muscle can regulate blood vessel density to match metabolic needs; however, the molecular cues that coordinate these processes remain poorly understood. Here we report that the transcriptional coactivator peroxisome proliferator-activated receptor-γ coactivator-1ß (PGC-1ß), a potent regulator of mitochondrial biology, induces angiogenesis in skeletal muscle. PGC-1ß induces the expression of vascular endothelial growth factor (VEGF) in cell culture and in vivo. The induction of VEGF by PGC-1ß requires coactivation of the orphan nuclear receptor estrogen-related receptor-α (ERRα) and is independent of the hypoxia-inducible factor (HIF) pathway. In coculture experiments, overexpression of PGC-1ß in skeletal myotubes increases the migration of adjacent endothelial cells, and this depends on VEGF signaling. Transgenic expression of PGC-1ß in skeletal myocytes dramatically increases muscular vessel density. Taken together, these data indicate that PGC-1ß is a potent regulator of angiogenesis, thus providing a novel link between the regulations of oxidative metabolism and vascular density.
Assuntos
Proteínas de Transporte/fisiologia , Músculo Esquelético/irrigação sanguínea , Músculo Esquelético/metabolismo , Neovascularização Fisiológica/genética , Animais , Proteínas de Transporte/genética , Proteínas de Transporte/metabolismo , Movimento Celular/genética , Movimento Celular/fisiologia , Células Cultivadas , Células Endoteliais/metabolismo , Células Endoteliais/fisiologia , Regulação da Expressão Gênica/genética , Humanos , Subunidade alfa do Fator 1 Induzível por Hipóxia/genética , Subunidade alfa do Fator 1 Induzível por Hipóxia/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/fisiologia , Proteínas de Ligação a RNA , Receptores de Estrogênio/genética , Receptores de Estrogênio/fisiologia , Fator A de Crescimento do Endotélio Vascular/genética , Fator A de Crescimento do Endotélio Vascular/metabolismo , Receptor ERRalfa Relacionado ao EstrogênioRESUMO
Stroke is a leading cause of death and disability. The only therapy available is recombinant tissue plasminogen activator, but side effects limit its use. Platelets play a crucial role during stroke, and the inflammatory reaction promotes neurodegeneration. von Willebrand factor (VWF), an adhesion molecule for platelets, is elevated in patients with acute stroke. The activity of VWF is modulated by ADAMTS13 (a disintegrin-like and metalloprotease with thrombospondin type I repeats-13) that cleaves VWF to smaller less-active forms. We recently documented that ADAMTS13 negatively regulates both thrombosis and inflammation. We report that deficiency or reduction of VWF reduces infarct volume up to 2-fold after focal cerebral ischemia in mice, thus showing the importance of VWF in stroke injury. In contrast, ADAMTS13 deficiency results in larger infarctions, but only in mice that have VWF. Importantly, infusion of a high dose of recombinant human ADAMTS13 into a wild-type mouse immediately before reperfusion reduces infarct volume and improves functional outcome without producing cerebral hemorrhage. Furthermore, recombinant ADAMTS13 did not enhance bleeding in a hemorrhagic stroke model. Our findings show the importance of VWF in regulating infarction and suggest that recombinant ADAMTS13 could be considered as a new therapeutic agent for prevention and/or treatment of stroke.
Assuntos
Proteínas ADAM/farmacologia , Hipóxia-Isquemia Encefálica/enzimologia , Hipóxia-Isquemia Encefálica/prevenção & controle , Metaloendopeptidases/metabolismo , Acidente Vascular Cerebral/enzimologia , Acidente Vascular Cerebral/prevenção & controle , Proteína ADAMTS13 , Animais , Humanos , Hipóxia-Isquemia Encefálica/genética , Metaloendopeptidases/genética , Camundongos , Camundongos Knockout , Proteínas Recombinantes/farmacologia , Fator de von Willebrand/genética , Fator de von Willebrand/metabolismoRESUMO
Cerebrovascular and cardiovascular diseases are a major cause of morbidity and mortality. Soluble P-selectin (sP-selectin) is a biomarker for platelet/endothelial activation and is considered a risk factor for vascular disease. sP-selectin enhances procoagulant activity by inducing leukocyte-derived microparticle production and promotes activation of leukocyte integrins. However, it is not known whether it directly contributes to vascular complications. We investigated the effect of increased levels of sP-selectin on blood-brain barrier (BBB) function, stroke outcome, and atherosclerosis by comparing wild-type mice with P-sel(DeltaCT/DeltaCT) mice in which the endogenous P-selectin gene was replaced with a mutant that produces abnormally high plasma levels of sP-selectin. P-sel(DeltaCT/DeltaCT) mice presented several abnormalities, including (1) higher BBB permeability, with 25% of the animals showing differential permeability between the right and left hemispheres; (2) altered social behavior with increased aggression; (3) larger infarcts in the middle cerebral artery occlusion ischemic stroke model; and (4) increased susceptibility to atherosclerotic, macrophage-rich lesion development in both male and female mice on the apoE(-/-) genetic background. Thus, elevated sP-selectin is not only a biomarker for vascular disease, but also may contribute directly to atherosclerosis and cerebrovascular complications.
Assuntos
Aterosclerose/sangue , Barreira Hematoencefálica/metabolismo , Infarto Cerebral/sangue , Selectina-P/sangue , Animais , Apolipoproteínas E/deficiência , Apolipoproteínas E/genética , Apolipoproteínas E/metabolismo , Aterosclerose/patologia , Infarto Cerebral/patologia , Feminino , Masculino , Camundongos , Selectina-P/genética , SolubilidadeRESUMO
The peroxiredoxin (Prdx) family of antioxidant enzymes uses redox-active cysteines to reduce peroxides, lipid hydroperoxides, and peroxynitrites. Prdx1 is known to be important to protect red blood cells against reactive oxygen species and in tumor prevention. In this study, the role of Prdx1 in inflammation, thrombosis, and atherosclerosis was investigated. Using intravital microscopy, we showed that the number of leukocytes rolling per minute in unstimulated veins was increased by 2.5-fold in Prdx1(-/-) compared to Prdx1(+/+) mice. In Prdx1(-/-) mice, 50% of leukocytes rolled at a velocity <10 mum/sec compared with 10% in Prdx1(+/+) mice, suggesting that adhesion molecule density on the endothelium may have been increased by Prdx1 deficiency. Indeed, endothelial P-selectin, soluble P-selectin, and von Willebrand factor in plasma were increased in Prdx1(-/-) mice compared to Prdx1(+/+) mice, indicating elevated Weibel-Palade body release. In contrast to this excessive endothelial activation, Prdx1(-/-) platelets showed no sign of hyperreactivity, and their aggregation both in vitro and in vivo was normal. We also examined the role of Prdx1 in the apoE(-/-) murine spontaneous model of atherosclerosis. Prdx1(-/-)/apoE(-/-) mice fed normal chow developed larger, more macrophage-rich aortic sinus lesions than Prdx1(+/+)/apoE(-/-) mice, despite similar amounts and size distributions of cholesterol in their plasma lipoproteins. Thus, Prdx1 protects against excessive endothelial activation and atherosclerosis, and the Prdx1(-/-) mice could serve as an animal model susceptible to chronic inflammation.
Assuntos
Aterosclerose/enzimologia , Aterosclerose/prevenção & controle , Endotélio Vascular/enzimologia , Endotélio Vascular/patologia , Mediadores da Inflamação/fisiologia , Peroxirredoxinas/fisiologia , Animais , Antioxidantes/fisiologia , Aterosclerose/genética , Aterosclerose/patologia , Modelos Animais de Doenças , Feminino , Predisposição Genética para Doença , Migração e Rolagem de Leucócitos/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Peroxirredoxinas/deficiência , Peroxirredoxinas/genéticaRESUMO
OBJECTIVE: Motivated by the central roles that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-beta play in the assembly and maintenance of the vasculature, we examined the impact of systemic VEGF or TGF-beta signal inhibition on endothelial activation as detected by leukocyte-endothelial interactions. METHODS AND RESULTS: VEGF or TGF-beta inhibition, accomplished using adenovirus expression of soluble Flt1 (Ad-sFlt1) or soluble endoglin (Ad-sEng), resulted in a significant increase in the number of leukocytes rolling along the mesenteric venous endothelium and a significant decrease in rolling velocity in Ad-sEng mice. Neutralization of VEGF or TGF-beta resulted in endothelial surface expression of P-selectin and impaired peripheral vasodilatation. Neither inhibition of VEGF nor TGF-beta was associated with platelet or leukocyte activation, as detected by the activation markers platelet P-selectin and the active integrin alphaIIbbetaIII, or by leukocyte expression of L-selectin. Soluble vascular cell adhesion molecule (VCAM)-1 and E-selectin were increased in sEng-expressing mice, indicating higher levels of these adhesion receptors. CONCLUSIONS: VEGF or TGF-beta neutralization leads to impaired endothelium-mediated vasodilatation and elevated expression of surface adhesion molecules, resulting in increased leukocyte adhesion. These results indicate an essential role for both VEGF and TGF-beta in maintaining the endothelium in a nonactivated state and have implications for therapeutic approaches that neutralize VEGF or TGF-beta.
Assuntos
Endotélio Vascular/citologia , Leucócitos/metabolismo , Transdução de Sinais/fisiologia , Fator de Crescimento Transformador beta/antagonistas & inibidores , Fator A de Crescimento do Endotélio Vascular/antagonistas & inibidores , Vasodilatação/fisiologia , Animais , Adesão Celular , Selectina E/biossíntese , Endotélio Vascular/metabolismo , Contagem de Leucócitos , Leucócitos/citologia , Veias Mesentéricas/citologia , Veias Mesentéricas/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Selectina-P/biossíntese , Fator de Crescimento Transformador beta/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Background: Injury to the articular surface of the distal radius commonly occurs after a fall onto an outstretched hand. Intra-articular fractures that cause joint depression require operative intervention and can be especially challenging in skeletally immature patients. Methods: This case report describes the use of an osteoarticular autograft in the treatment of a 13-year-old boy with a malunited distal radius fracture. Results: Osteoarticular transfer from the lateral femoral condyle provided definitive treatment of the malunion and physeal bar and resulted in significant improvement in range of motion. Conclusions: Osteoarticular autograft can be safely used to treat malunions of distal radius articular surface depression fractures in skeletally immature patients.
Assuntos
Fraturas do Rádio , Osso Escafoide , Adolescente , Osso e Ossos , Criança , Humanos , Masculino , Radiografia , Rádio (Anatomia) , Fraturas do Rádio/diagnóstico por imagem , Fraturas do Rádio/cirurgiaRESUMO
Objectives: Smoking has been associated with poor cuff healing and worse long-term outcomes in patients undergoing rotator cuff repair. The effects of smoking on short-term complications following open rotator cuff repair are not well defined. The purpose of this study is to analyze the effects of smoking on 30-day outcomes following open rotator cuff repair. Methods: The American College of Surgeons National Surgical Quality Improvement Program was used to identify patients who underwent open rotator cuff repair from 2011 to 2016. Patients who were current smokers (within 1 year prior to surgery) were identified and compared with nonsmokers. Demographic data and postoperative complications within 30 days were analyzed. Multivariable logistic regression was used to isolate the effect of smoking on complications after surgery. Results: We identified 5,157 patients who underwent open rotator cuff repair, of which 18% (946 patients) were current smokers (within 1 year of surgery). Smokers were younger (54.4 years versus 61.5 years, P < 0.001) and were more likely to be male (60.8% versus 56.9%, P = 0.03). Compared with nonsmokers, smokers had a similar rate of comorbidities (P = 0.35) and similar preoperative functional status (P = 0.53), but had higher mean American Society of Anesthesiologists (ASA) class (P < 0.001). Logistic regression revealed that smoking was an independent predictor for any complication (OR 1.9, P = 0.03), any venous thromboembolic event (OR 4.6, P = 0.01), and pulmonary embolism (OR 6.4, P = 0.02). Conclusion: Patients who smoke are at increased risk for short-term complications after open rotator cuff repair. Smoking is independently associated with increased rate of postoperative venous thromboembolic events such as pulmonary embolism. This further highlights the importance of preoperative smoking cessation in patients undergoing open rotator cuff repair.
Assuntos
Complicações Pós-Operatórias , Lesões do Manguito Rotador/complicações , Lesões do Manguito Rotador/cirurgia , Fumar/efeitos adversos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Embolia Pulmonar/etiologia , Fatores de Risco , Manguito Rotador/cirurgia , Tromboembolia Venosa/etiologiaRESUMO
We have previously shown that activated platelets in circulation stimulate release of endothelial Weibel-Palade bodies thus increasing leukocyte rolling in venules. P-selectin on the activated platelets mediates adhesion to leukocytes via PSGL-1 and is rapidly shed into plasma. We were interested in studying the role of PSGL-1 in regulating expression and function of platelet P-selectin. We show here that PSGL-1 is critical for the activation of endothelial cells in venules of mice infused with activated platelets. The interaction of platelet P-selectin with PSGL-1 is also required for P-selectin shedding, as P-selectin was retained significantly longer on the surface of activated platelets infused into PSGL-1(-/-) compared to wild-type mice. The leukocyte integrin alphaMbeta2 (Mac-1) was not required for P-selectin shedding. In addition to shedding, P-selectin can be downregulated from the platelet surface through internalization and this is the predominant mechanism in the absence of PSGL-1. We demonstrate that leukocyte-neutrophil elastase, known to cleave P-selectin in vitro, is not the major sheddase for P-selectin in vivo. In conclusion, interaction of platelet P-selectin with PSGL-1 is crucial for activation of the endothelium andWeibel-Palade body secretion. The interaction with PSGL-1 also results in rapid shedding of P-selectin thus downregulating the inflammatory potential of the platelet.
Assuntos
Endotélio/metabolismo , Regulação da Expressão Gênica , Glicoproteínas de Membrana/fisiologia , Selectina-P/sangue , Ativação Plaquetária , Corpos de Weibel-Palade/imunologia , Animais , Plaquetas/metabolismo , Ensaio de Imunoadsorção Enzimática , Feminino , Elastase de Leucócito/metabolismo , Leucócitos/enzimologia , Leucócitos/metabolismo , Masculino , Glicoproteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Selectina-P/metabolismo , Corpos de Weibel-Palade/metabolismoRESUMO
BACKGROUND: Duchenne muscle dystrophy (DMD) afflicts 1 million boys in the US and has few effective treatments. Constitutive transgenic expression of the transcriptional coactivator peroxisome proliferator-activated receptor gamma coactivator (PGC)-1α improves skeletal muscle function in the murine "mdx" model of DMD, but how this occurs, or whether it can occur post-natally, is not known. The leading mechanistic hypotheses for the benefits conferred by PGC-1α include the induction of utrophin, a dystrophin homolog, and/or induction and stabilization of the neuromuscular junction. METHODS: The effects of transgenic overexpression of PGC-1ß, a homolog of PGC-1α in mdx mice was examined using different assays of skeletal muscle structure and function. To formally test the hypothesis that PGC-1α confers benefit in mdx mice by induction of utrophin and stabilization of neuromuscular junction, PGC-1α transgenic animals were crossed with the dystrophin utrophin double knock out (mdx/utrn-/-) mice, a more severe dystrophic model. Finally, we also examined the effect of post-natal induction of skeletal muscle-specific PGC-1α overexpression on muscle structure and function in mdx mice. RESULTS: We show here that PGC-1ß does not induce utrophin or other neuromuscular genes when transgenically expressed in mouse skeletal muscle. Surprisingly, however, PGC-1ß transgenesis protects as efficaciously as PGC-1α against muscle degeneration in dystrophin-deficient (mdx) mice, suggesting that alternate mechanisms of protection exist. When PGC-1α is overexpressed in mdx/utrn-/- mice, we find that PGC-1α dramatically ameliorates muscle damage even in the absence of utrophin. Finally, we also used inducible skeletal muscle-specific PGC-1α overexpression to show that PGC-1α can protect against dystrophy even if activated post-natally, a more plausible therapeutic option. CONCLUSIONS: These data demonstrate that PGC-1α can improve muscle dystrophy post-natally, highlighting its therapeutic potential. The data also show that PGC-1α is equally protective in the more severely affected mdx/utrn-/- mice, which more closely recapitulates the aggressive progression of muscle damage seen in DMD patients. The data also identify PGC-1ß as a novel potential target, equally efficacious in protecting against muscle dystrophy. Finally, the data also show that PGC-1α and PGC-1ß protect against dystrophy independently of utrophin or of induction of the neuromuscular junction, indicating the existence of other mechanisms.
RESUMO
The transcriptional coactivators PGC-1α and PGC-1ß are widely thought to be required for mitochondrial biogenesis and fiber typing in skeletal muscle. Here, we show that mice lacking both PGC-1s in myocytes do indeed have profoundly deficient mitochondrial respiration but, surprisingly, have preserved mitochondrial content, isolated muscle contraction capacity, fiber-type composition, in-cage ambulation, and voluntary running capacity. Most of these findings are recapitulated in cell culture and, thus, are cell autonomous. Functional electron microscopy reveals normal cristae density with decreased cytochrome oxidase activity. These data lead to the following surprising conclusions: (1) PGC-1s are in fact dispensable for baseline muscle function, mitochondrial content, and fiber typing, (2) endurance fatigue at low workloads is not limited by muscle mitochondrial capacity, and (3) mitochondrial content and cristae density can be dissociated from respiratory capacity.
Assuntos
Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Fatores de Transcrição/metabolismo , Animais , Linhagem Celular , Complexo de Proteínas da Cadeia de Transporte de Elétrons/metabolismo , Complexo IV da Cadeia de Transporte de Elétrons/metabolismo , Camundongos , Camundongos Knockout , Microscopia Eletrônica , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Fatores de Transcrição/deficiência , Fatores de Transcrição/genéticaRESUMO
The beating heart consumes more ATP per weight than any other organ. The machineries required for this are many and complex. Fuel and oxygen must be transported via the vasculature, absorbed by cardiomyocytes, broken down, and regulated to match cellular demands. Much of this occurs in mitochondria, which comprise fully one third of cardiac mass. The PGC-1 proteins are transcriptional coactivators that have emerged as powerful orchestrators of these numerous processes, ensuring their proper coregulation in response to intracellular and extracellular cues. An important role for PGC-1s in cardiac function has been revealed over the past few years, and more recently interest in their role in the vasculature has been burgeoning. We review this literature, focusing on recent developments.
Assuntos
Sistema Cardiovascular/metabolismo , Proteínas de Transporte/fisiologia , Coração/fisiologia , Proteínas de Choque Térmico/fisiologia , Fatores de Transcrição/fisiologia , Trifosfato de Adenosina/metabolismo , Animais , Sistema Cardiovascular/efeitos dos fármacos , Expressão Gênica/efeitos dos fármacos , Insuficiência Cardíaca/fisiopatologia , Proteínas de Choque Térmico/uso terapêutico , Humanos , Mitocôndrias Cardíacas/efeitos dos fármacos , Mitocôndrias Cardíacas/fisiologia , Miocárdio/metabolismo , Miócitos Cardíacos/metabolismo , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Processamento de Proteína Pós-Traducional , Proteínas de Ligação a RNA , Fatores de Transcrição/uso terapêutico , Fator A de Crescimento do Endotélio Vascular/biossínteseRESUMO
Exercise confers numerous health benefits, many of which are thought to stem from exercise-induced mitochondrial biogenesis (EIMB) in skeletal muscle. The transcriptional coactivator PGC-1α, a potent regulator of metabolism in numerous tissues, is widely believed to be required for EIMB. We show here that this is not the case. Mice engineered to lack PGC-1α specifically in skeletal muscle (Myo-PGC-1αKO mice) retained intact EIMB. The exercise capacity of these mice was comparable to littermate controls. Induction of metabolic genes after 2 weeks of in-cage voluntary wheel running was intact. Electron microscopy revealed no gross abnormalities in mitochondria, and the mitochondrial biogenic response to endurance exercise was as robust in Myo-PGC-1αKO mice as in wildtype mice. The induction of enzymatic activity of the electron transport chain by exercise was likewise unperturbed in Myo-PGC-1αKO mice. These data demonstrate that PGC-1α is dispensable for exercise-induced mitochondrial biogenesis in skeletal muscle, in sharp contrast to the prevalent assumption in the field.