Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic–pituitary–adrenal axis

Braun, Theodore P.; Zhu, Xiao‐Dong; Szumowski, Marek; Scott, Gregory D.; Grossberg, Aaron J.; Levasseur, Peter R.; Graham, Kathryn; Khan, Sumsullah; Damaraju, Sambasivarao; Colmers, William F.; Baracos, Vickie E.; Marks, Daniel L.

doi:10.1084/jem.20111020

Cited by 180 publications

(205 citation statements)

References 76 publications

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“…The induction of inflammation is most pronounced in the hypothalamus and is not observed in other brain structures such as the cerebral cortex ( Figure 5B). In alignment with previous findings that muscle atrophy during inflammatory stimuli is mediated by hypothalamic–pituitary–adrenal activation, end‐stage KPC‐engrafted animals demonstrate a 1.77 ± 0.19‐fold increase in hypothalamic expression of corticotropin‐releasing hormone ( P < 0.05) ( Figure 5C) 22, 26…”

Section: Resultssupporting

confidence: 90%

“…Muscles with a high preponderance of fast‐twitch fibres, that is, gastrocnemius, tibialis anterior, and quadriceps, were selected for skeletal muscle analysis because they are particularly susceptible to wasting in inflammatory states 26. Indeed, KPC tumour growth induced tissue atrophy in all three of these muscle groups, corresponding to high expression levels of the ubiquitin ligases MAFBx and MuRF1 and their transcriptional inducer FOXO1.…”

Section: Discussionmentioning

confidence: 99%

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Establishment and characterization of a novel murine model of pancreatic cancer cachexia

Michaelis

Zhu

Burfeind

et al. 2017

J cachexia sarcopenia muscle

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119

161

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BackgroundCachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC‐associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D P53R172H Pdx‐Cre+/+ (KPC) mouse.MethodsMale and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development.ResultsAll routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil‐dominant leukocytosis and anaemia, and decreased serum testosterone.ConclusionsSyngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies.

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

Michaelis

Zhu

Burfeind

et al. 2017

J cachexia sarcopenia muscle

Self Cite

119

161

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“…Numerous reports have documented the potential contribution of GC (32), proinflammatory cytokines (33,34), and LPS (35) to this effect. However, recent studies have substantially evidenced that GC were indeed requisite to this process, because activation of the genes involved in muscle atrophy after LPS-induced peripheral inflammation was essentially blocked by adrenalectomy (36). In this study, we observed a strong reduction in the activation of catabolic genes but also of repressor genes of the mTOR anabolic pathway in muscle of endotoxemic hypomSR-BI DAC mice.…”

Section: Discussionsupporting

confidence: 56%

Adrenocortical Scavenger Receptor Class B Type I Deficiency Exacerbates Endotoxic Shock and Precipitates Sepsis-Induced Mortality in Mice

Gilibert

Galle-Treger

Moreau

et al. 2014

The Journal of Immunology

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Scavenger receptor class B type I (SR-BI)–deficient mice display reduced survival to endotoxic shock and sepsis. The understanding of the mechanisms underlying SR-BI protection has been hampered by the large spectrum of SR-BI functions and ligands. It notably plays an important role in the liver in high-density lipoprotein metabolism, but it is also thought to participate in innate immunity as a pattern recognition receptor for bacterial endotoxins, such as LPS. In this study, we sought to determine the tissue-specific contribution of SR-BI in the hyperinflammatory response and high mortality rates observed in SR-BI−/− mice in endotoxicosis or sepsis. Restoring plasma levels of high-density lipoprotein, which are critical lipoproteins for LPS neutralization, did not improve acute outcomes of LPS injection in SR-BI−/− mice. Mice deficient for SR-BI in hepatocytes, endothelial cells, or myeloid cells were not more susceptible to LPS-induced death. However, if SR-BI ablation in hepatocytes led to a moderate increase in systemic inflammatory markers, SR-BI deficiency in myeloid cells was associated with an anti-inflammatory effect. Finally, mice deficient for SR-BI in the adrenal cortex, where the receptor provides lipoprotein-derived cholesterol, had impaired secretion of glucocorticoids in response to stress. When exposed to an endotoxin challenge, these mice exhibited an exacerbated systemic and local inflammatory response, reduced activation of atrophy genes in muscle, and high lethality rate. Furthermore, polymicrobial sepsis induced by cecal ligature and puncture resulted in early death of these animals. Our study clearly demonstrates that corticoadrenal SR-BI is a critical element of the hypothalamic-pituitary-adrenal axis to provide effective glucocorticoid-dependent host defense after an endotoxic shock or bacterial infection.

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“…Interestingly, brain-IL1B injection leads to muscle wasting and increases in markers of muscle protein breakdown, such as MURF and Atrogin1. In accordance with the existance of an adrenal-mediated effect, adrenalectomy suppressed IL1B-induced muscle atrophy, whilst glucocorticoid treatment was enough to promote muscle atrophy (Braun et al 2011). Interestingly, in spite of muscle wasting induced by cancer, uremia, or LPS, as well as IL1B-induced anorexia is suppressed by MC4R blockade (Marks et al 2001, 2003, Wisse et al 2001, Cheung et al 2008, Whitaker & Reyes 2008), MC4R-knockout animals are not saved from body lean mass loss after central infusion of IL1B (Braun et al 2011), these findings indicate that different neuronal circuits are involved in the CNS modulation of muscle catabolic programs and that the hypothalamus is crucial for induction and maintenance of the main symptoms of cancer cachexia.…”

Section: Neuroendocrine Regulation Of Cachexia-induced Thermogenesis mentioning

confidence: 53%

“…Although the influence of the hypothalamus on the modutation of lean body mass is clear, the mechanisms are only partially elucidated (Marks et al 2001, 2003, Wisse et al 2001, Cheung et al 2008, Braun et al 2011. The hypothalamic-pituitary-adrenal axis is an important Figure 2 The hypothalamus is at the crossroads of cancer cachexia's main features.…”

Section: Neuroendocrine Regulation Of Cachexia-induced Thermogenesis mentioning

confidence: 99%

Molecular and neuroendocrine mechanisms of cancer cachexia

Mendes

Pimentel

Costa

et al. 2015

Journal of Endocrinology

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Cancer and its morbidities, such as cancer cachexia, constitute a major public health problem. Although cancer cachexia has afflicted humanity for centuries, its underlying multifactorial and complex physiopathology has hindered the understanding of its mechanism. During the last few decades we have witnessed a dramatic increase in the understanding of cancer cachexia pathophysiology. Anorexia and muscle and adipose tissue wasting are the main features of cancer cachexia. These apparently independent symptoms have humoral factors secreted by the tumor as a common cause. Importantly, the hypothalamus has emerged as an organ that senses the peripheral signals emanating from the tumoral environment, and not only elicits anorexia but also contributes to the development of muscle and adipose tissue loss. Herein, we review the roles of factors secreted by the tumor and its effects on the hypothalamus, muscle and adipose tissue, as well as highlighting the key targets that are being exploited for cancer cachexia treatment.

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Central nervous system inflammation induces muscle atrophy via activation of the hypothalamic–pituitary–adrenal axis

Abstract: Systemic and CNS-delimited inflammation triggers skeletal muscle catabolism in a manner dependent on glucocorticoid signaling.

Cited by 180 publications

References 76 publications

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

Establishment and characterization of a novel murine model of pancreatic cancer cachexia

Adrenocortical Scavenger Receptor Class B Type I Deficiency Exacerbates Endotoxic Shock and Precipitates Sepsis-Induced Mortality in Mice

Molecular and neuroendocrine mechanisms of cancer cachexia

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