Dataset Information

Derangements of amino acids in cachectic skeletal muscle are caused by mitochondrial dysfunction.

ABSTRACT:

Background

Cachexia is the direct cause of at least 20% of cancer-associated deaths. Muscle wasting in skeletal muscle results in weakness, immobility, and death secondary to impaired respiratory muscle function. Muscle proteins are massively degraded in cachexia; nevertheless, the molecular mechanisms related to this process are poorly understood. Previous studies have reported conflicting results regarding the amino acid abundances in cachectic skeletal muscle tissues. There is a clear need to identify the molecular processes of muscle metabolism in the context of cachexia, especially how different types of molecules are involved in the muscle wasting process.

Methods

New in situ -omics techniques were used to produce a more comprehensive picture of amino acid metabolism in cachectic muscles by determining the quantities of amino acids, proteins, and cellular metabolites. Using matrix-assisted laser desorption/ionization (MALDI) mass spectrometry imaging, we determined the in situ concentrations of amino acids and proteins, as well as energy and other cellular metabolites, in skeletal muscle tissues from genetic mouse cancer models (n = 21) and from patients with cancer (n = 6). Combined results from three individual MALDI mass spectrometry imaging methods were obtained and interpreted. Immunohistochemistry staining for mitochondrial proteins and myosin heavy chain expression, digital image analysis, and transmission electron microscopy complemented the MALDI mass spectrometry imaging results.

Results

Metabolic derangements in cachectic mouse muscle tissues were detected, with significantly increased quantities of lysine, arginine, proline, and tyrosine (P = 0.0037, P = 0.0048, P = 0.0430, and P = 0.0357, respectively) and significantly reduced quantities of glutamate and aspartate (P = 0.0008 and P = 0.0124). Human skeletal muscle tissues revealed similar tendencies. A majority of altered amino acids were released by the breakdown of proteins involved in oxidative phosphorylation. Decreased energy charge was observed in cachectic muscle tissues (P = 0.0101), which was related to the breakdown of specific proteins. Additionally, expression of the cationic amino acid transporter CAT1 was significantly decreased in the mitochondria of cachectic mouse muscles (P = 0.0133); this decrease may play an important role in the alterations of cationic amino acid metabolism and decreased quantity of glutamate observed in cachexia.

Conclusions

Our results suggest that mitochondrial dysfunction has a substantial influence on amino acid metabolism in cachectic skeletal muscles, which appears to be triggered by diminished CAT1 expression, as well as the degradation of mitochondrial proteins. These findings provide new insights into the pathobiochemistry of muscle wasting.

SUBMITTER: Kunzke T

PROVIDER: S-EPMC7015243 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Publications

Derangements of amino acids in cachectic skeletal muscle are caused by mitochondrial dysfunction.

Kunzke Thomas T Buck Achim A Prade Verena M VM Feuchtinger Annette A Prokopchuk Olga O Martignoni Marc E ME Heisz Simone S Hauner Hans H Janssen Klaus-Peter KP Walch Axel A Aichler Michaela M

Journal of cachexia, sarcopenia and muscle 20191113 1

<h4>Background</h4>Cachexia is the direct cause of at least 20% of cancer-associated deaths. Muscle wasting in skeletal muscle results in weakness, immobility, and death secondary to impaired respiratory muscle function. Muscle proteins are massively degraded in cachexia; nevertheless, the molecular mechanisms related to this process are poorly understood. Previous studies have reported conflicting results regarding the amino acid abundances in cachectic skeletal muscle tissues. There is a clear ...[more]

PMID: 31965747

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Project description:Skeletal muscle mitochondrial dysfunction is secondary to T2DM and can be improved by long-term regular exercise training Mitochondrial dysfunction has long been implicated to play a causative role in development of type 2 diabetes (T2DM). However, a growing number of recent studies provide data that mitochondrial dysfunction is a consequence of T2DM development. The aim of our study is to clarify in further detail the causal role of mitochondrial dysfunction in T2DM by a comprehensive ex vivo analysis of mitochondrial function combined with global gene expression analysis in muscle of pre-diabetic newly diagnosed untreated T2DM subjects and long-standing insulin treated T2DM subjects compared with age- and BMI-matched controls. In addition, we assessed the impact of long-term interval exercise training on physical activity performance, mitochondrial function and glycemic control in long-standing insulin-treated T2DM subjects. Ex vivo mitochondrial density, quality and functioning was comparable between pre-diabetic subjects and matched controls, however, gene expression analysis showed a switch from carbohydrate toward lipids as energy source in pre-diabetes subjects. In contrast, long-term insulin treated T2DM subjects had slightly decreased mitochondrial density and ex vivo function. Expression of Krebs cycle and OXPHOS related genes were decreased, indicating a decreased capacity to use lipids as an energy source. The insulin-treated T2DM subjects had a lower physical activity level than pre-diabetic and normoglycemic subjects. A 52 weeks exercise training of these subjects increased submaximal oxidative efficiency, increased in vivo PCr recovery rate, as well as mildly increased in vitro mitochondrial function. Gene expression of β-oxidation, Krebs cycle and OXPHOS-related genes was increased. Our data demonstrate that mitochondrial dysfunction is rather a consequence than a causative factor in T2DM development as it was only detected in overt diabetes and not in early diabetes. Regular exercise training stabilized exogenous insulin requirement and improved mitochondrial functioning, fatty acid oxidation and general physical work load capacity in long-standing insulin-treated T2DM subjects. As such, the present study shows for the first time that long-term exercise interventions are beneficial in this group of complex diabetes patient and may prevent further metabolic deterioration.

Project description:BackgroundCachexia is a complex metabolic disorder and muscle atrophy syndrome, impacting 80% patients with advanced cancers. Malignant glioma is considered to be one of the deadliest human cancers, accounting for about 60% of all primary brain tumors. However, cachexia symptoms induced by glioma have received little attention. This work aims to explore skeletal muscle atrophy in orthotopic glioma murine models.MethodsBALB/c nude mice were orthotopicly implanted with normal glial (HEB) and glioma (WHO II CHG5 and WHO IV U87) cells. Cachexia symptoms of mice were depicted by phenotypic, histopathologic, physiological, and biochemical analyses. Muscle atrophy-related proteins were examined by western blot, and the involved signaling pathways were analyzed. NMR-based metabolomic analysis was applied to profile metabolic derangements in the skeletal muscle, including multivariate statistical analysis, characteristic metabolite identification, and metabolic pathway analysis.ResultsCompared with controls, mice implanted with glioma cells exhibit typical cachexia symptoms, indicating a high correlation with the malignant grades of glioma. U87 mice develop cachexia much earlier and more severe than CHG5 mice. The glioma-bearing mice showed significantly decreased skeletal muscle mass and strength, which were associated with suppressed AKT, activated AMPK, FOXO, Atrogin1, and LC3. Interestingly, expressions of MuRF1, MyoD1, and eIF3f were not significantly changed. Consistently, metabolomic analyses elucidate pronounced metabolic derangements in cachectic gastrocnemius relative to controls. Glucose, glycerol, and 3-hydroxybutyrate were remarkably downregulated, whereas glutamate, arginine, leucine, and isoleucine were upregulated in cachectic gastrocnemius. Furthermore, U87 mice showed more characteristic metabolites and more disturbed metabolic pathways including glucose and lipid metabolism, protein catabolism, anabolism, and citric acid cycle anaplerotic.ConclusionsThis study demonstrates for the first time that the orthotopic glioma murine model developed here exhibits high fidelity of cachexia manifestations in two malignant grades of glioma. Signaling pathway analysis in combination with metabolomic analysis provides significant insights into the complex pathophysiology of glioma cachexia and expands understanding of the molecular mechanisms underlying muscle atrophy.

Dataset Information

Derangements of amino acids in cachectic skeletal muscle are caused by mitochondrial dysfunction.

Background

Methods

Results

Conclusions

Publications

Derangements of amino acids in cachectic skeletal muscle are caused by mitochondrial dysfunction.

Similar Datasets

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