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Nude mice orthotopicly implanted with human glioma cell lines

ABSTRACT: Malignant gliomas are considered to be one of the deadliest human cancers, accounting for about 60% of all primary brain tumors. Cachexia is a complex metabolic derangement and muscle atrophy syndrome, which causes high mortalities in patients with advanced cancers including brain tumors. However, cachexia symptoms induced by gliomas and mechanisms underlying muscle atrophy are unclear. Herein, we developed a glioma cachexia model using nude mice orthotopicly implanted with two glioma cell lines (WHO II CHG5 and WHO IV U87). U87 mice developed more severe cachexia symptoms than CHG5 mice, including more evident anorexia, greater body weight loss and mortality. Unlike non-central nervous system cancer cachexia, glioma cachexia did not induce remarkable systemic inflammation but massive multi-organ atrophy. It also caused significantly decreased skeletal muscle mass and strength, which were associated with down-regulated myosin and AKT, and up-regulated AMPK, FOXO and Atrogin1. Interestingly, expressions of MuRF1, MyoD1, eIF3f, desmin and vimentin were not significantly changed. Consistently, NMR-based metabolomic analyses revealed pronounced metabolic derangements in cachectic gastrocnemius relative to controls. Glucose, glycerol, 3-hydroxybutyrate and glycine were remarkably down-regulated, whereas largely released amino acids due to proteolysis including glutamate, arginine, leucine and isoleucine were up-regulated in cachectic gastrocnemius. Moreover, glucose and lipid metabolism, protein biosynthesis and amino acid metabolism were disturbed dramatically in both glioma-bearing mice. U87 mice showed more changed metabolite levels and altered metabolic pathways. This work uncovers malignant grade-dependent glioma cachexia symptoms and metabolic derangements of skeletal muscle for the first time, and provides hints for new therapeutic approaches.

ORGANISM(S): Mouse Mus Musculus

TISSUE(S): Muscle

DISEASE(S): Cachexia

SUBMITTER: Pengfei Cui

PROVIDER: ST001064 | MetabolomicsWorkbench | Sat Sep 22 00:00:00 BST 2018

REPOSITORIES: MetabolomicsWorkbench

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Project description:Background: Cancer cachexia (CAC) reduces patient survival and quality of life. Developments of efficient therapeutic strategies are required for the CAC treatments. This long-term process could be shortened by the drug-repositioning approach which exploits old drugs approved for non-cachexia disease. Amiloride, a diuretic drug, is clinically used for treatments of hypertension and edema due to heart failure. Here, we explored the effects of amiloride for ameliorating muscle wasting in murine models of cancer cachexia. Methods: CT26 and LLC tumor cells were subcutaneously injected into mice to induce cancer cachexia. Amiloride was intraperitoneally injected daily once tumors were formed. Cachexia features of the CT26 and LLC models, respectively, were characterized by phenotypic, histopathologic and biochemical analyses. Plasma exosomes and muscle atrophy-related proteins were quantitatively analyzed. Integrative NMR-based metabolomic and transcriptomic analyses were conducted to identify significantly altered metabolic pathways and distinctly changed metabolism-related biological processes in gastrocnemius. Results: The CT26 and LLC models displayed prominent cachexia features including decreases in body weight, skeletal muscle, adipose tissue and muscle strength. The amiloride treatment in tumor-bearing mice distinctly alleviated muscle atrophy and relieved cachexia-related features without affecting tumor growth. The CT26 and LLC cachexia mice showed increased particle density of plasma exosomes which were largely derived from tumors. Significantly, the amiloride treatment inhibited tumor-derived exosome release, which did not obviously affect exosome secretion from non-neoplastic tissues or induce observable systemic toxicities in normal healthy mice. Integrative-omics revealed significant metabolic impairments in cachectic gastrocnemius, including promoted muscular catabolism, inhibited muscular protein synthesis, blocked glycolysis and impeded ketone body oxidation. The amiloride treatment evidently improved the metabolic impairments in cachectic gastrocnemius. Conclusions: Our results demonstrated the efficacy of amiloride in ameliorating cachectic muscle wasting and elucidated the underlying mechanistic rationale for its use as an alternative strategy to improve CAC treatments.

Project description:Skeletal muscle atrophy is a consequence of many diseases, environmental insults, inactivity, age and injury. Atrophy is characterized by active degradation and removal of contractile proteins and a reduction in fiber size. Animal models have been extensively used to identify pathways leading to atrophic conditions. Here we have used genome-wide expression profiling analysis and quantitative PCR to identify the molecular changes that occur in two clinically relevant animal mouse models of muscle atrophy, hindlimb casting and Achilles tendon laceration (tenotomy). Gastrocnemius muscle samples were collected 2, 7 and 14 days after insult. The total amount of muscle loss as measured by wet weight and muscle fiber size was equivalent between models, although tenotomy resulted in a more rapid induction of muscle atrophy. Furthermore, tentomy resulted in the regulation of significantly more mRNA transcripts then casting. Analysis of the regulated genes and pathways suggest that the mechanism of atrophy is distinct between these models. The degradation following casting appears ubiquitin-proteasome-mediated while degradation following tenotomy appears lysosomal and matrix-metalloproteinase (MMP)-mediated. This data suggests that there are multiple mechanisms leading to muscle atrophy and that specific therapeutic agents may be necessary to combat the atrophy seen under different conditions. Muscle atrophy was induced through two methods; unloading induced by tendon laceration (Tenotomy) and immobilization induced by hindlimb casting (Casting). For the tenotomy, eight week old male C57/B6 mice were anesthetized by ether inhalation and subsequent intramuscular injection of ketamine-xylazine (0.1 ml/g). The right Achilles tendon just proximal to the calcaneus was severed with a sterile scalpel. The mice were allowed to recover and move freely about their cage. An additional cohort of animals was sham operated (Sham) which involved isolation and manipulation of the Achilles tendon without laceration. For the casting, the right hindlimbs of eight week old male C57Bl/6 mice were immobilized through casting. After 2, 7 or 14 days, animals were sacrificed and the left and right gastrocnemius muscles were carefully removed, flash frozen in liquid nitrogen, and stored at -80°C for further processing. The left untreated legs served as controls. A group of naïve animals that received no treatment or manipulation was included as an additional control. Each group consisted of between 5 and 10 samples for a total of 111 individual samples.

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Nude mice orthotopicly implanted with human glioma cell lines

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