RESUMO
Age-related loss of skeletal muscle innervation by motor neurons leads to impaired neuromuscular function and is a well-established clinical phenomenon. However, the underlying pathogenesis remains unclear. Studying mice, we find that the number of motor units (MUs) can be maintained by counteracting neurotoxic microglia in the aged spinal cord. We observe that marked innervation changes, detected by motor unit number estimation (MUNE), occur prior to loss of muscle function in aged mice. This coincides with gene expression changes indicative of neuronal remodeling and microglial activation in aged spinal cord. Voluntary exercise prevents loss of MUs and reverses microglia activation. Depleting microglia by CSF1R inhibition also prevents the age-related decline in MUNE and neuromuscular junction disruption, implying a causal link. Our results suggest that age-related changes in spinal cord microglia contribute to neuromuscular decline in aged mice and demonstrate that removal of aged neurotoxic microglia can prevent or reverse MU loss.
Assuntos
Envelhecimento/metabolismo , Microglia/metabolismo , Neurônios Motores/metabolismo , Condicionamento Físico Animal/fisiologia , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/antagonistas & inibidores , Envelhecimento/patologia , Animais , Linhagem Celular , Bases de Dados Genéticas , Humanos , Células-Tronco Pluripotentes Induzidas , Macrófagos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microglia/enzimologia , Microglia/fisiologia , Neurônios Motores/citologia , Neurônios Motores/patologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiopatologia , Junção Neuromuscular/metabolismo , Plasticidade Neuronal/genética , RNA-Seq , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/genética , Receptores de Fator Estimulador das Colônias de Granulócitos e Macrófagos/metabolismo , Medula Espinal/enzimologia , Medula Espinal/metabolismo , Medula Espinal/fisiopatologiaRESUMO
The majority of patients with advanced cancer suffer from cachexia, a systemic wasting syndrome, which subsequently impacts the tolerance to anti-cancer treatments, response to therapy, quality of life, and eventually, survival. Despite a high unmet medical need, there is currently no specific remedy available for an effective treatment of cachexia and its sequelae. A key feature of cachexia is the inexorable loss of skeletal muscle mass, which constitutes a main contributor to body weight loss and progressive functional impairments. Therefore, it's crucial to identify early readouts to detect and monitor the loss of muscle mass and function to initiate appropriate treatments timely. Here, we describe experimental cancer models using mouse (syngeneic) or human (xenograft) cancer cell lines with a rapid onset of tumor growth and cachexia. These models are easier to establish, monitor and reproduce compared to the genetically engineered mouse models currently available. Moreover, we establish readouts such as hind limb muscle mass and volume, as well as evoked force and food intake measurements, to allow the evaluation of potential therapeutic agents for the early treatment of cachexia and associated impairments.
Assuntos
Caquexia/etiologia , Caquexia/patologia , Músculo Esquelético/patologia , Neoplasias/complicações , Animais , Peso Corporal , Caquexia/diagnóstico por imagem , Linhagem Celular Tumoral , Neoplasias do Colo/complicações , Modelos Animais de Doenças , Humanos , Extremidade Inferior/diagnóstico por imagem , Imageamento por Ressonância Magnética , Melanoma/complicações , Camundongos , Músculo Esquelético/diagnóstico por imagemRESUMO
Metallothioneins are proteins that are involved in intracellular zinc storage and transport. Their expression levels have been reported to be elevated in several settings of skeletal muscle atrophy. We therefore investigated the effect of metallothionein blockade on skeletal muscle anabolism in vitro and in vivo We found that concomitant abrogation of metallothioneins 1 and 2 results in activation of the Akt pathway and increases in myotube size, in type IIb fiber hypertrophy, and ultimately in muscle strength. Importantly, the beneficial effects of metallothionein blockade on muscle mass and function was also observed in the setting of glucocorticoid addition, which is a strong atrophy-inducing stimulus. Given the blockade of atrophy and the preservation of strength in atrophy-inducing settings, these results suggest that blockade of metallothioneins 1 and 2 constitutes a promising approach for the treatment of conditions which result in muscle atrophy.
Assuntos
Metalotioneína/metabolismo , Força Muscular/fisiologia , Músculo Esquelético/metabolismo , Animais , Biomarcadores/metabolismo , Peso Corporal , Tamanho Celular , Inativação Gênica , Glucocorticoides/efeitos adversos , Humanos , Hipertrofia , Camundongos , Desenvolvimento Muscular , Fibras Musculares Esqueléticas/metabolismo , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Atrofia Muscular , Tamanho do Órgão , Proteínas Proto-Oncogênicas c-akt/metabolismo , Ratos , Sarcopenia/metabolismo , Sarcopenia/patologia , Sarcopenia/fisiopatologia , Transdução de Sinais , Serina-Treonina Quinases TOR/metabolismo , Regulação para Cima , Zinco/metabolismoRESUMO
BACKGROUND: Cachexia affects the majority of patients with advanced cancer and is associated with reduced treatment tolerance, response to therapy, quality of life, and life expectancy. Cachectic patients with advanced cancer often receive anti-cancer therapies against their specific cancer type as a standard of care, and whether specific ActRII inhibition is efficacious when combined with anti-cancer agents has not been elucidated yet. METHODS: In this study, we evaluated interactions between ActRII blockade and anti-cancer agents in CT-26 mouse colon cancer-induced cachexia model. CDD866 (murinized version of bimagrumab) is a neutralizing antibody against the activin receptor type II (ActRII) preventing binding of ligands such as myostatin and activin A, which are involved in cancer cachexia. CDD866 was evaluated in association with cisplatin as a standard cytotoxic agent or with everolimus, a molecular-targeted agent against mammalian target of rapamycin (mTOR). In the early studies, the treatment effect on cachexia was investigated, and in the additional studies, the treatment effect on progression of cancer and the associated cachexia was evaluated using body weight loss or tumor volume as interruption criteria. RESULTS: Cisplatin accelerated body weight loss and tended to exacerbate skeletal muscle loss in cachectic animals, likely due to some toxicity of this anti-cancer agent. Administration of CDD866 alone or in combination with cisplatin protected from skeletal muscle weight loss compared to animals receiving only cisplatin, corroborating that ActRII inhibition remains fully efficacious under cisplatin treatment. In contrast, everolimus treatment alone significantly protected the tumor-bearing mice against skeletal muscle weight loss caused by CT-26 tumor. CDD866 not only remains efficacious in the presence of everolimus but also showed a non-significant trend for an additive effect on reversing skeletal muscle weight loss. Importantly, both combination therapies slowed down time-to-progression. CONCLUSIONS: Anti-ActRII blockade is an effective intervention against cancer cachexia providing benefit even in the presence of anti-cancer therapies. Co-treatment comprising chemotherapies and ActRII inhibitors might constitute a promising new approach to alleviate chemotherapy- and cancer-related wasting conditions and extend survival rates in cachectic cancer patients.
Assuntos
Receptores de Activinas Tipo II/antagonistas & inibidores , Receptores de Activinas Tipo II/metabolismo , Anticorpos Bloqueadores/administração & dosagem , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Caquexia/prevenção & controle , Neoplasias do Colo/complicações , Receptores de Activinas Tipo II/imunologia , Animais , Anticorpos Monoclonais Humanizados , Peso Corporal/efeitos dos fármacos , Caquexia/etiologia , Cisplatino/administração & dosagem , Modelos Animais de Doenças , Progressão da Doença , Everolimo/administração & dosagem , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Serina-Treonina Quinases TOR/metabolismo , Carga Tumoral/efeitos dos fármacosRESUMO
The peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) controls metabolic adaptations. We now show that PGC-1α in skeletal muscle drives the expression of lactate dehydrogenase (LDH) B in an estrogen-related receptor-α-dependent manner. Concomitantly, PGC-1α reduces the expression of LDH A and one of its regulators, the transcription factor myelocytomatosis oncogene. PGC-1α thereby coordinately alters the composition of the LDH complex and prevents the increase in blood lactate during exercise. Our results show how PGC-1α actively coordinates lactate homeostasis and provide a unique molecular explanation for PGC-1α-mediated muscle adaptations to training that ultimately enhance exercise performance and improve metabolic health.
Assuntos
Receptor alfa de Estrogênio/metabolismo , Regulação Enzimológica da Expressão Gênica/fisiologia , Homeostase/fisiologia , L-Lactato Desidrogenase/biossíntese , Ácido Láctico/sangue , Proteínas Musculares/metabolismo , Músculo Esquelético/metabolismo , Transativadores/metabolismo , Animais , Linhagem Celular , Receptor alfa de Estrogênio/genética , Isoenzimas/biossíntese , Isoenzimas/genética , L-Lactato Desidrogenase/genética , Lactato Desidrogenase 5 , Camundongos , Camundongos Knockout , Proteínas Musculares/genética , Músculo Esquelético/citologia , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Condicionamento Físico Animal , Transativadores/genética , Fatores de TranscriçãoRESUMO
Catch-up growth, a risk factor for type 2 diabetes, is characterized by hyperinsulinemia and accelerated body fat recovery. Using a rat model of semistarvation-refeeding that exhibits catch-up fat, we previously reported that during refeeding on a low-fat diet, glucose tolerance is normal but insulin-dependent glucose utilization is decreased in skeletal muscle and increased in adipose tissue, where de novo lipogenic capacity is concomitantly enhanced. Here we report that isocaloric refeeding on a high-fat (HF) diet blunts the enhanced in vivo insulin-dependent glucose utilization for de novo lipogenesis (DNL) in adipose tissue. These are shown to be early events of catch-up growth that are independent of hyperphagia and precede the development of overt adipocyte hypertrophy, adipose tissue inflammation, or defective insulin signaling. These results suggest a role for enhanced DNL as a glucose sink in regulating glycemia during catch-up growth, which is blunted by exposure to an HF diet, thereby contributing, together with skeletal muscle insulin resistance, to the development of glucose intolerance. Our findings are presented as an extension of the Randle cycle hypothesis, whereby the suppression of DNL constitutes a mechanism by which dietary lipids antagonize glucose utilization for storage as triglycerides in adipose tissue, thereby impairing glucose homeostasis during catch-up growth.
Assuntos
Adipócitos/metabolismo , Tecido Adiposo/metabolismo , Glucose/metabolismo , Homeostase/fisiologia , Lipogênese/fisiologia , Síndrome da Realimentação/metabolismo , Adipócitos/patologia , Tecido Adiposo/patologia , Animais , Dieta Hiperlipídica , Hiperinsulinismo/metabolismo , Hiperfagia/metabolismo , Hipertrofia/metabolismo , Hipertrofia/patologia , Hipoglicemiantes/farmacologia , Insulina/farmacologia , Masculino , Ratos , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologiaRESUMO
Skeletal muscle exhibits a high plasticity and accordingly can quickly adapt to different physiological and pathological stimuli by changing its phenotype largely through diverse epigenetic mechanisms. The nuclear receptor corepressor 1 (NCoR1) has the ability to mediate gene repression; however, its role in regulating biological programs in skeletal muscle is still poorly understood. We therefore studied the mechanistic and functional aspects of NCoR1 function in this tissue. NCoR1 muscle-specific knockout mice exhibited a 7.2% higher peak oxygen consumption (VO(2peak)), a 11% reduction in maximal isometric force, and increased ex vivo fatigue resistance during maximal stimulation. Interestingly, global gene expression analysis revealed a high overlap between the effects of NCoR1 deletion and peroxisome proliferator-activated receptor gamma (PPARγ) coactivator 1α (PGC-1α) overexpression on oxidative metabolism in muscle. Importantly, PPARß/δ and estrogen-related receptor α (ERRα) were identified as common targets of NCoR1 and PGC-1α with opposing effects on the transcriptional activity of these nuclear receptors. In fact, the repressive effect of NCoR1 on oxidative phosphorylation gene expression specifically antagonizes PGC-1α-mediated coactivation of ERRα. We therefore delineated the molecular mechanism by which a transcriptional network controlled by corepressor and coactivator proteins determines the metabolic properties of skeletal muscle, thus representing a potential therapeutic target for metabolic diseases.