RESUMO
Mechanical ventilation (MV) is used to support ventilation and pulmonary gas exchange in patients during critical illness and surgery. Although MV is a life-saving intervention for patients in respiratory failure, an unintended side-effect of MV is the rapid development of diaphragmatic atrophy and contractile dysfunction. This MV-induced diaphragmatic weakness is labelled as 'ventilator-induced diaphragm dysfunction' (VIDD). VIDD is an important clinical problem because diaphragmatic weakness is a risk factor for the failure to wean patients from MV. Indeed, the inability to remove patients from ventilator support results in prolonged hospitalization and increased morbidity and mortality. The pathogenesis of VIDD has been extensively investigated, revealing that increased mitochondrial production of reactive oxygen species within diaphragm muscle fibres promotes a cascade of redox-regulated signalling events leading to both accelerated proteolysis and depressed protein synthesis. Together, these events promote the rapid development of diaphragmatic atrophy and contractile dysfunction. This review highlights the MV-induced changes in the structure/function of diaphragm muscle and discusses the cell-signalling mechanisms responsible for the pathogenesis of VIDD. This report concludes with a discussion of potential therapeutic opportunities to prevent VIDD and suggestions for future research in this exciting field.
RESUMO
Calpains are cysteine proteases expressed in skeletal muscle fibers and other cells. Although calpain was first reported to act as a kinase activating factor in skeletal muscle, the consensus is now that calpains play a canonical role in protein turnover. However, recent evidence reveals new and exciting roles for calpains in skeletal muscle. This review will discuss the functions of calpains in skeletal muscle remodeling in response to both exercise and inactivity-induced muscle atrophy. Calpains participate in protein turnover and muscle remodeling by selectively cleaving target proteins and creating fragmented proteins that can be further degraded by other proteolytic systems. Nonetheless, an often overlooked function of calpains is that calpain-mediated cleavage of proteins can result in fragmented proteins that are biologically active and have the potential to actively influence cell signaling. In this manner, calpains function beyond their roles in protein turnover and influence downstream signaling effects. This review will highlight both the canonical and noncanonical roles that calpains play in skeletal muscle remodeling including sarcomere transformation, membrane repair, triad junction formation, regulation of excitation-contraction coupling, protein turnover, cell signaling, and mitochondrial function. We conclude with a discussion of key unanswered questions regarding the roles that calpains play in skeletal muscle.
Assuntos
Calpaína/metabolismo , Exercício Físico/fisiologia , Músculo Esquelético/metabolismo , Atrofia Muscular/metabolismo , Animais , Calpaína/química , Membrana Celular/metabolismo , Humanos , Mitocôndrias Musculares/metabolismo , Fibras Musculares Esqueléticas/metabolismo , Atrofia Muscular/etiologia , Oxirredução , Fosforilação , Isoformas de Proteínas/metabolismo , Proteólise , Sarcômeros/metabolismo , Comportamento Sedentário , Transdução de SinaisRESUMO
Repeated bouts of endurance exercise promotes numerous biochemical adaptations in skeletal muscle fibers resulting in a muscle phenotype that is protected against a variety of homeostatic challenges; these exercise-induced changes in muscle phenotype are often referred to as "exercise preconditioning." Importantly, exercise preconditioning provides protection against several threats to skeletal muscle health including cancer chemotherapy (e.g., doxorubicin) and prolonged muscle inactivity. This review summarizes our current understanding of the mechanisms responsible for exercise-induced protection of skeletal muscle fibers against both doxorubicin-induced muscle wasting and a unique form of inactivity-induced muscle atrophy (i.e., ventilator-induced diaphragm atrophy). Specifically, the first section of this article will highlight the potential mechanisms responsible for exercise-induced protection of skeletal muscle fibers against doxorubicin-induced fiber atrophy. The second segment will discuss the biochemical changes that are responsible for endurance exercise-mediated protection of diaphragm muscle against ventilator-induced diaphragm wasting. In each section, we highlight gaps in our knowledge in hopes of stimulating future research in this evolving field of investigation.
Assuntos
Doxorrubicina/efeitos adversos , Exercício Físico/fisiologia , Músculo Esquelético/fisiologia , Atrofia Muscular/fisiopatologia , Resistência Física/fisiologia , Animais , Humanos , Músculo Esquelético/efeitos dos fármacos , Atrofia Muscular/induzido quimicamente , Condicionamento Físico Animal/fisiologiaRESUMO
Prolonged skeletal muscle inactivity (e.g. limb immobilization, bed rest, mechanical ventilation, spinal cord injury, etc.) results in muscle atrophy that manifests into a decreased quality of life and in select patient populations, a higher risk of morbidity and mortality. Thus, understanding the processes that contribute to muscle atrophy during prolonged periods of muscle disuse is an important area of research. In this regard, mitochondrial dysfunction has been directly linked to the muscle wasting that occurs during extended periods of skeletal muscle inactivity. While the concept that mitochondrial dysfunction contributes to disuse muscle atrophy has been contemplated for nearly 50 years, the mechanisms connecting mitochondrial signaling events to skeletal muscle atrophy remained largely unexplained until recently. Indeed, emerging evidence reveals that mitochondrial dysfunction and the associated mitochondrial signaling events are a requirement for several forms of inactivity-induced skeletal muscle atrophy. Specifically, inactivity-induced alterations in skeletal muscle mitochondria phenotype and increased ROS emission, impaired Ca2+ handling, and release of mitochondria-specific proteolytic activators are established occurrences that promote fiber atrophy during prolonged periods of muscle inactivity. This review highlights the evidence that directly connects mitochondrial dysfunction and aberrant mitochondrial signaling with skeletal muscle atrophy and discusses the mechanisms linking these interconnected phenomena.
Assuntos
Mitocôndrias Musculares/fisiologia , Atrofia Muscular/fisiopatologia , Comportamento Sedentário , Animais , Metabolismo Energético , Homeostase , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Qualidade de Vida , Espécies Reativas de Oxigênio/metabolismo , Transdução de SinaisRESUMO
The renin-angiotensin system (RAS) plays a key role in the control of blood pressure and fluid homeostasis. Emerging evidence also reveals that hyperactivity of the RAS contributes to skeletal muscle wasting. This review discusses the key role that the RAS plays in skeletal muscle wasting due to congestive heart failure, chronic kidney disease, and ventilator-induced diaphragmatic wasting.
Assuntos
Músculo Esquelético/fisiopatologia , Atrofia Muscular/fisiopatologia , Sistema Renina-Angiotensina , Animais , Diafragma/fisiopatologia , Insuficiência Cardíaca/fisiopatologia , Humanos , Insuficiência Renal Crônica/fisiopatologia , Respiração Artificial/efeitos adversosRESUMO
The existence of free radicals in living cells was first reported in 1954 and this important finding helped launch the field of free radical biology. However, the discovery that muscular exercise is associated with increased biomarkers of oxidative stress did not occur until 1978. Following the initial report that exercise promotes oxidative stress in humans, many studies have confirmed that prolonged or short-duration high intensity exercise results in increased radical production in active skeletal muscles resulting in the formation of oxidized lipids and proteins in the working muscles. Since these early descriptive studies, the investigation of radicals and redox biology related to exercise and skeletal muscle has grown as a discipline and the importance of this research in the biomedical sciences is widely recognized. This review will briefly summarize the history of research in exercise-induced oxidative stress and will discuss the major paradigm shifts that the field has undergone and continues to experience. We conclude with a discussion of future directions in the hope of stimulating additional research in this important field.
Assuntos
Exercício Físico/fisiologia , Estresse Oxidativo/fisiologia , Animais , Humanos , Contração Muscular , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Espécies Reativas de Oxigênio/metabolismoRESUMO
Although doxorubicin (DOX) is a highly effective anti-tumour agent used to treat a variety of cancers, DOX administration is associated with significant side effects, including myopathy of both cardiac and skeletal muscles. The mechanisms responsible for DOX-mediated myopathy remain a topic of debate. We tested the hypothesis that both increased mitochondrial reactive oxygen species (ROS) emission and activation of the cysteine protease calpain are required for DOX-induced myopathy in rat cardiac and skeletal muscle. Cause and effect was determined by administering a novel mitochondrial-targeted anti-oxidant to prevent DOX-induced increases in mitochondrial ROS emission, whereas a highly-selective pharmacological inhibitor was exploited to inhibit calpain activity. Our findings reveal that mitochondria are a major site of DOX-mediated ROS production in both cardiac and skeletal muscle fibres and the prevention of DOX-induced increases in mitochondrial ROS emission protects against fibre atrophy and contractile dysfunction in both cardiac and skeletal muscles. Furthermore, our results indicate that DOX-induced increases in mitochondrial ROS emission are required to activate calpain in heart and skeletal muscles and, importantly, calpain activation is a major contributor to DOX-induced myopathy. Taken together, these findings show that increased mitochondrial ROS production and calpain activation are significant contributors to the development of DOX-induced myopathy in both cardiac and skeletal muscle fibres.
Assuntos
Calpaína/metabolismo , Doxorrubicina/farmacologia , Mitocôndrias/metabolismo , Músculo Esquelético/metabolismo , Doenças Musculares/metabolismo , Miocárdio/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Feminino , Coração/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/patologia , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Doenças Musculares/induzido quimicamente , Doenças Musculares/patologia , Miocárdio/patologia , Estresse Oxidativo/efeitos dos fármacos , Ratos , Ratos Sprague-DawleyRESUMO
Myocardial ischemia-reperfusion (IR) injury can cause ventricular cell death and is a major pathological event leading to morbidity and mortality in those with coronary artery disease. Interestingly, as few as five bouts of exercise on consecutive days can rapidly produce a cardiac phenotype that resists IR-induced myocardial injury. This review summarizes the development of exercise-induced cardioprotection and the mechanisms responsible for this important adaptive response.
Assuntos
Exercício Físico/fisiologia , Coração/fisiologia , Traumatismo por Reperfusão Miocárdica/prevenção & controle , Miocárdio/metabolismo , Animais , Doença da Artéria Coronariana/prevenção & controle , Coração/fisiopatologia , Humanos , Proteínas Mitocondriais/metabolismo , Traumatismo por Reperfusão Miocárdica/etiologia , Traumatismo por Reperfusão Miocárdica/fisiopatologiaRESUMO
OBJECTIVES: Mechanical ventilation is a lifesaving measure for patients with respiratory failure. However, prolonged mechanical ventilation results in diaphragm weakness, which contributes to problems in weaning from the ventilator. Therefore, identifying the signaling pathways responsible for mechanical ventilation-induced diaphragm weakness is essential to developing effective countermeasures to combat this important problem. In this regard, the forkhead boxO family of transcription factors is activated in the diaphragm during mechanical ventilation, and forkhead boxO-specific transcription can lead to enhanced proteolysis and muscle protein breakdown. Currently, the role that forkhead boxO activation plays in the development of mechanical ventilation-induced diaphragm weakness remains unknown. DESIGN: This study tested the hypothesis that mechanical ventilation-induced increases in forkhead boxO signaling contribute to ventilator-induced diaphragm weakness. SETTING: University research laboratory. SUBJECTS: Young adult female Sprague-Dawley rats. INTERVENTIONS: Cause and effect was determined by inhibiting the activation of forkhead boxO in the rat diaphragm through the use of a dominant-negative forkhead boxO adeno-associated virus vector delivered directly to the diaphragm. MEASUREMENTS AND MAIN RESULTS: Our results demonstrate that prolonged (12 hr) mechanical ventilation results in a significant decrease in both diaphragm muscle fiber size and diaphragm-specific force production. However, mechanically ventilated animals treated with dominant-negative forkhead boxO showed a significant attenuation of both diaphragm atrophy and contractile dysfunction. In addition, inhibiting forkhead boxO transcription attenuated the mechanical ventilation-induced activation of the ubiquitin-proteasome system, the autophagy/lysosomal system, and caspase-3. CONCLUSIONS: Forkhead boxO is necessary for the activation of key proteolytic systems essential for mechanical ventilation-induced diaphragm atrophy and contractile dysfunction. Collectively, these results suggest that targeting forkhead boxO transcription could be a key therapeutic target to combat ventilator-induced diaphragm dysfunction.
Assuntos
Diafragma/fisiopatologia , Fatores de Transcrição Forkhead/antagonistas & inibidores , Respiração Artificial/efeitos adversos , Animais , Diafragma/patologia , Feminino , Hemodinâmica , Contração Muscular , Atrofia Muscular , Proteínas do Tecido Nervoso , Ratos , Ratos Sprague-Dawley , Transdução de SinaisRESUMO
Controlled mechanical ventilation (CMV) is associated with the development of diaphragm atrophy and contractile dysfunction, and respiratory muscle weakness is thought to contribute significantly to delayed weaning of patients. Therefore, therapeutic strategies for preventing these processes may have clinical benefit. The aim of the current study was to investigate the role of the Janus kinase (JAK)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in CMV-mediated diaphragm wasting and weakness in rats. CMV-induced diaphragm atrophy and contractile dysfunction coincided with marked increases in STAT3 phosphorylation on both tyrosine 705 (Tyr705) and serine 727 (Ser727). STAT3 activation was accompanied by its translocation into mitochondria within diaphragm muscle and mitochondrial dysfunction. Inhibition of JAK signaling during CMV prevented phosphorylation of both target sites on STAT3, eliminated the accumulation of phosphorylated STAT3 within the mitochondria, and reversed the pathologic alterations in mitochondrial function, reduced oxidative stress in the diaphragm, and maintained normal diaphragm contractility. In addition, JAK inhibition during CMV blunted the activation of key proteolytic pathways in the diaphragm, as well as diaphragm atrophy. These findings implicate JAK/STAT3 signaling in the development of diaphragm muscle atrophy and dysfunction during CMV and suggest that the delayed extubation times associated with CMV can be prevented by inhibition of Janus kinase signaling.-Smith, I. J., Godinez, G. L., Singh, B. K., McCaughey, K. M., Alcantara, R. R., Gururaja, T., Ho, M. S., Nguyen, H. N., Friera, A. M., White, K. A., McLaughlin, J. R., Hansen, D., Romero, J. M., Baltgalvis, K. A., Claypool, M. D., Li, W., Lang, W., Yam, G. C., Gelman, M. S., Ding, R., Yung, S. L., Creger, D. P., Chen, Y., Singh, R., Smuder, A. J., Wiggs, M. P., Kwon, O.-S., Sollanek, K. J., Powers, S. K., Masuda, E. S., Taylor, V. C., Payan, D. G., Kinoshita, T., Kinsella, T. M. Inhibition of Janus kinase signaling during controlled mechanical ventilation prevents ventilation-induced diaphragm dysfunction.
Assuntos
Diafragma/metabolismo , Janus Quinases/metabolismo , Respiração Artificial/efeitos adversos , Transdução de Sinais/fisiologia , Animais , Interleucina-6/metabolismo , Masculino , Mitocôndrias/metabolismo , Debilidade Muscular/metabolismo , Atrofia Muscular/metabolismo , Estresse Oxidativo/fisiologia , Fosforilação/fisiologia , Proteólise , Ratos , Ratos Sprague-Dawley , Fator de Transcrição STAT3/metabolismo , Serina/metabolismo , Tirosina/metabolismoRESUMO
OBJECTIVES: Diaphragm dysfunction develops during severe sepsis as a consequence of hemodynamic, metabolic, and intrinsic abnormalities. Similarly, 12 hours of controlled mechanical ventilation also promotes diaphragm dysfunction. Importantly, patients with sepsis are often treated with mechanical ventilation for several days. It is unknown if controlled mechanical ventilation exacerbates sepsis-induced diaphragm dysfunction, and this forms the basis for these experiments. We investigate the effects of 12-hour controlled mechanical ventilation on contractile function, fiber dimension, cytokine production, proteolysis, autophagy, and oxidative stress in the diaphragm of septic rats. DESIGN: Randomized controlled experiment. SETTING: Animal research laboratory. SUBJECTS: Adult male Wistar rats. INTERVENTIONS: Treatment with a single intraperitoneal injection of either saline or Escherichia coli lipopolysaccharide (5 mg/kg). After 12 hours, the saline-treated animals (controlled mechanical ventilation) and half of the septic animals (lipopolysaccharide + controlled mechanical ventilation) were submitted to 12 hours of controlled mechanical ventilation while the remaining septic animals (lipopolysaccharide) were breathing spontaneously for 12 hours. They were compared to a control group. All animals were studied 24 hours after saline or lipopolysaccharide administration. MEASUREMENTS AND MAIN RESULTS: Twenty-four hours after saline or lipopolysaccharide administration, diaphragm contractility was measured in vitro. We also measured diaphragm muscle fiber dimensions from stained cross sections, and inflammatory cytokines were determined by proteome array. Activities of calpain, caspase-3, and proteasome, expression of 20S-proteasome α subunits, E2 conjugases, E3 ligases, and autophagy were measured with immunoblotting and quantitative polymerase chain reaction. Lipopolysaccharide and/or controlled mechanical ventilation independently decreased diaphragm contractility and fiber dimensions and increased diaphragm interleukin-6 production, protein ubiquitination, expression of Atrogin-1 and Murf-1, calpain and caspase-3 activities, autophagy, and protein oxidation. Compared with lipopolysaccharide alone, lipopolysaccharide + controlled mechanical ventilation worsened diaphragm contractile dysfunction, augmented diaphragm interleukin-6 levels, autophagy, and protein oxidation, but exerted no exacerbating effects on diaphragm fiber dimensions, calpain, caspase-3, or proteasome activation. CONCLUSIONS: Twelve hours of controlled mechanical ventilation potentiates sepsis-induced diaphragm dysfunction, possibly due to increased proinflammatory cytokine production and autophagy and worsening of oxidative stress.
Assuntos
Autofagia/fisiologia , Citocinas/metabolismo , Diafragma/fisiopatologia , Respiração Artificial/efeitos adversos , Sepse/fisiopatologia , Doenças Torácicas/fisiopatologia , Animais , Immunoblotting , Lipopolissacarídeos/farmacologia , Masculino , Contração Muscular/fisiologia , Estresse Oxidativo/fisiologia , Reação em Cadeia da Polimerase , Proteólise , Ratos , Ratos WistarRESUMO
Cancer cachexia is characterized by a continuous loss of locomotor skeletal muscle mass, which causes profound muscle weakness. If this atrophy and weakness also occurs in diaphragm muscle, it could lead to respiratory failure, which is a major cause of death in patients with cancer. Thus, the purpose of the current study was to determine whether colon-26 (C-26) cancer cachexia causes diaphragm muscle fiber atrophy and weakness and compromises ventilation. All diaphragm muscle fiber types were significantly atrophied in C-26 mice compared to controls, and the atrophy-related genes, atrogin-1 and MuRF1, significantly increased. Maximum isometric specific force of diaphragm strips, absolute maximal calcium activated force, and maximal specific calcium-activated force of permeabilized diaphragm fibers were all significantly decreased in C-26 mice compared to controls. Further, isotonic contractile properties of the diaphragm were affected to an even greater extent than isometric function. Ventilation measurements demonstrated that C-26 mice have a significantly lower tidal volume compared to controls under basal conditions and, unlike control mice, an inability to increase breathing frequency, tidal volume, and, thus, minute ventilation in response to a respiratory challenge. These data demonstrate that C-26 cancer cachexia causes profound respiratory muscle atrophy and weakness and ventilatory dysfunction.
Assuntos
Caquexia/fisiopatologia , Neoplasias do Colo/fisiopatologia , Diafragma/fisiopatologia , Atrofia Muscular/fisiopatologia , Insuficiência Respiratória/fisiopatologia , Actinas/metabolismo , Animais , Western Blotting , Caquexia/etiologia , Linhagem Celular Tumoral , Neoplasias do Colo/complicações , Diafragma/metabolismo , Diafragma/patologia , Expressão Gênica , Imuno-Histoquímica , Camundongos , Proteínas Musculares/genética , Debilidade Muscular/etiologia , Debilidade Muscular/fisiopatologia , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Atrofia Muscular/etiologia , Cadeias Pesadas de Miosina/metabolismo , Insuficiência Respiratória/etiologia , Músculos Respiratórios/metabolismo , Músculos Respiratórios/patologia , Músculos Respiratórios/fisiopatologia , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Proteínas Ligases SKP Culina F-Box/genética , Proteínas com Motivo Tripartido , Tropomiosina/metabolismo , Troponina/metabolismo , Ubiquitina-Proteína Ligases/genéticaRESUMO
BACKGROUND: Mechanical ventilation (MV) is a life-saving intervention in patients with acute respiratory failure. However, prolonged MV results in ventilator-induced diaphragm dysfunction (VIDD), a condition characterized by both diaphragm fiber atrophy and contractile dysfunction. Previous work has shown that calpain, caspase-3, and the ubiquitin-proteasome pathway (UPP) are all activated in the diaphragm during prolonged MV. However, although it is established that both calpain and caspase-3 are important contributors to VIDD, the role that the UPP plays in the development of VIDD remains unknown. These experiments tested the hypothesis that inhibition of the UPP will protect the diaphragm against VIDD. METHODS: The authors tested this prediction in an established animal model of MV using a highly specific UPP inhibitor, epoxomicin, to prevent MV-induced activation of the proteasome in the diaphragm (n = 8 per group). RESULTS: The results of this study reveal that inhibition of the UPP did not prevent ventilator-induced diaphragm muscle fiber atrophy and contractile dysfunction during 12 h of MV. Also, inhibition of the UPP does not affect MV-induced increases in calpain and caspase-3 activity in the diaphragm. Finally, administration of the proteasome inhibitor did not protect against the MV-induced increases in the expression of the E3 ligases, muscle ring finger-1 (MuRF1), and atrogin-1/MaFbx. CONCLUSION: Collectively, these results indicate that proteasome activation does not play a required role in VIDD development during the first 12 h of MV.
Assuntos
Diafragma/patologia , Complexo de Endopeptidases do Proteassoma/efeitos dos fármacos , Ubiquitina/antagonistas & inibidores , Lesão Pulmonar Induzida por Ventilação Mecânica/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/patologia , Anestesia , Animais , Antibióticos Antineoplásicos/farmacologia , Atrofia , Western Blotting , Ácidos Borônicos/uso terapêutico , Bortezomib , Caspase 3/metabolismo , DNA Complementar/biossíntese , Feminino , Contração Muscular/efeitos dos fármacos , Proteínas Musculares/metabolismo , Oligopeptídeos/farmacologia , Inibidores de Proteases/uso terapêutico , Complexo de Endopeptidases do Proteassoma/genética , Proteólise/efeitos dos fármacos , Pirazinas/uso terapêutico , Ratos , Ratos Sprague-Dawley , Reação em Cadeia da Polimerase em Tempo Real , Respiração Artificial , Proteínas Ligases SKP Culina F-Box/metabolismo , Proteínas com Motivo Tripartido , Ubiquitina/genética , Ubiquitina-Proteína Ligases/metabolismo , Lesão Pulmonar Induzida por Ventilação Mecânica/genéticaRESUMO
BACKGROUND: Mechanical ventilation (MV) is a method of maintaining appropriate gas exchange in patients who are unable to sustain adequate alveolar ventilation. While lifesaving in the short-term, prolonged MV leads to altered cardiovascular responses and enhanced lung injury, but the exact mechanism is unknown. Therefore, we investigated the involvement of the sympathoadrenergic and renin-angiotensin system in MV-induced altered cardiovascular responses. METHODS: Sprague-Dawley rats were divided into six groups: (1) spontaneous breathing (SB); (2) SB + enalapril (100 µg/kg intravenous infusion); (3) SB + losartan (100 µg/kg infusion); (4) 12 h of MV; (5) MV + enalapril; and (6) MV + losartan. After the animals were sacrificed, blood and tissue samples were collected. Tyrosine hydroxylase, dopamine beta hydroxylase, and neuropeptide Y were measured in adrenal medulla and hypothalamus, whereas AT1 was measured in lung tissues by Western blot. Norepinephrine enzyme-linked immunosorbent assay and total antioxidant capacity were assayed in plasma. RESULTS: Our findings indicated that MV increases the sympathetic activation markers in adrenal medulla and hypothalamus. Moreover, oxidative stress was increased in lung and brain tissues. Treatment with enalapril or losartan reduced the lipid peroxidation in lung and brain tissues, while preserving the tissue glutathione content and plasma antioxidant capacity. CONCLUSIONS: These data demonstrate that the inhibition of the renin-angiotensin system by enalapril or losartan may reduce the MV-induced increase in sympathetic activity markers and oxidative stress, and thus, may have a beneficial effect as adjuvant therapy.
Assuntos
Medula Suprarrenal/metabolismo , Enalapril/farmacologia , Hipotálamo/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Respiração Artificial/efeitos adversos , Medula Suprarrenal/efeitos dos fármacos , Bloqueadores do Receptor Tipo 1 de Angiotensina II/farmacologia , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Animais , Enalapril/uso terapêutico , Feminino , Hipotálamo/efeitos dos fármacos , Losartan/farmacologia , Losartan/uso terapêutico , Pneumopatias/prevenção & controle , Ratos , Ratos Sprague-Dawley , Sistema Nervoso Simpático/efeitos dos fármacosRESUMO
INTRODUCTION: Immobilization of hindlimb muscles in a shortened position results in an accelerated rate of inactivity-induced muscle atrophy and contractile dysfunction. Similarly, prolonged controlled mechanical ventilation (CMV) results in diaphragm inactivity and induces diaphragm muscle atrophy and contractile dysfunction. Further, the application of positive end-expiratory airway pressure (PEEP) during mechanical ventilation would result in shortened diaphragm muscle fibers throughout the respiratory cycle. Therefore, we tested the hypothesis that, compared to CMV without PEEP, the combination of PEEP and CMV would accelerate CMV-induced diaphragm muscle atrophy and contractile dysfunction. To test this hypothesis, we combined PEEP with CMV or with assist-control mechanical ventilation (AMV) and determined the effects on diaphragm muscle atrophy and contractile properties. METHODS: The PEEP level (8 cmH2O) that did not induce lung overdistension or compromise circulation was determined. In vivo segmental length changes of diaphragm muscle fiber were then measured using sonomicrometry. Sedated rabbits were randomized into seven groups: surgical controls and those receiving CMV, AMV or continuous positive airway pressure (CPAP) with or without PEEP for 2 days. We measured in vitro diaphragmatic force, diaphragm muscle morphometry, myosin heavy-chain (MyHC) protein isoforms, caspase 3, insulin-like growth factor 1 (IGF-1), muscle atrophy F-box (MAFbx) and muscle ring finger protein 1 (MuRF1) mRNA. RESULTS: PEEP shortened end-expiratory diaphragm muscle length by 15%, 14% and 12% with CMV, AMV and CPAP, respectively. Combined PEEP and CMV reduced tidal excursion of segmental diaphragm muscle length; consequently, tidal volume (VT) decreased. VT was maintained with combined PEEP and AMV. CMV alone decreased maximum tetanic force (Po) production by 35% versus control (P < 0.01). Combined PEEP and CMV did not decrease Po further. Po was preserved with AMV, with or without PEEP. Diaphragm muscle atrophy did not occur in any fiber types. Diaphragm MyHC shifted to the fast isoform in the combined PEEP and CMV group. In both the CMV and combined PEEP and CMV groups compared to controls, IGF-1 mRNAs were suppressed, whereas Caspase-3, MAFbx and MuRF1 mRNA expression were elevated. CONCLUSIONS: Two days of diaphragm muscle fiber shortening with PEEP did not exacerbate CMV-induced diaphragm muscle dysfunction.
Assuntos
Diafragma/patologia , Respiração com Pressão Positiva , Respiração Artificial/efeitos adversos , Animais , Caspase 3/metabolismo , Diafragma/metabolismo , Masculino , Contração Muscular/fisiologia , Proteínas Musculares/metabolismo , Atrofia Muscular/metabolismo , Coelhos , Sistema RespiratórioRESUMO
Following the discovery that exercise increases the production of reactive oxygen species in contracting skeletal muscles, evidence quickly emerged that endurance exercise training increases the abundance of key antioxidant enzymes in the trained muscles. Since these early observations, knowledge about the impact that regular exercise has on skeletal muscle antioxidant capacity has increased significantly. Importantly, in recent years, our understanding of the cell signaling pathways responsible for this exercise-induced increase in antioxidant enzymes has expanded exponentially. Therefore, the goals of this review are: 1) summarize our knowledge about the influence that exercise training has on the abundance of key antioxidant enzymes in skeletal muscles; and 2) to provide a state-of-the-art review of the nuclear factor erythroid 2-related factor (Nrf2) signaling pathway that is responsible for many of the exercise-induced changes in muscle antioxidant capacity. We begin with a discussion of the sources of reactive oxygen species in contracting muscles and then examine the exercise-induced changes in the antioxidant enzymes that eliminate both superoxide radicals and hydrogen peroxide in muscle fibers. We conclude with a discussion of the advances in our understanding of the exercise-induced control of the Nrf2 signaling pathway that is responsible for the expression of numerous antioxidant proteins. In hopes of stimulating future research, we also identify gaps in our knowledge about the signaling pathways responsible for the exercise-induced increases in muscle antioxidant enzymes.
RESUMO
The discovery that contracting skeletal muscle generates reactive oxygen species (ROS) was first reported over 40 years ago. The prevailing view in the 1980s was that exercise-induced ROS production promotes oxidation of proteins and lipids resulting in muscle damage. However, a paradigm shift occurred in the 1990s as growing research revealed that ROS are signaling molecules, capable of activating transcriptional activators/coactivators and promoting exercise-induced muscle adaptation. Growing evidence supports the notion that reduction-oxidation (redox) signaling pathways play an important role in the muscle remodeling that occurs in response to endurance exercise training. This review examines the specific role that redox signaling plays in this endurance exercise-induced skeletal muscle adaptation. We begin with a discussion of the primary sites of ROS production in contracting muscle fibers followed by a summary of the antioxidant enzymes involved in the regulation of ROS levels in the cell. We then discuss which redox-sensitive signaling pathways promote endurance exercise-induced muscle adaptation and debate the strength of the evidence supporting the notion that redox signaling plays an essential role in muscle adaptation to endurance exercise training. In hopes of stimulating future research, we highlight several important unanswered questions in this field.