l-carnitine and cancer cachexia: Clinical and experimental aspects

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Abstract

Cancer cachexia is a multifaceted syndrome characterized, among many symptoms, by extensive muscle wasting. Chronic systemic inflammation, partly triggered and sustained by cytokines, as well as increased oxidative stress contributes to the pathogenesis of this complex metabolic disorder. l-carnitine plays a central role in the metabolism of fatty acids and shows important antioxidant and anti-inflammatory properties. Systemic carnitine depletion has been described in several diseases, and it is characterized by fatigue, muscle weakness, and decreased tolerance to metabolic stress. In cachectic cancer patients, low serum carnitine levels have been reported, and this change has been suggested to play an important contributory role in the development of cachexia. Based on these data, carnitine supplementation has been tested in preliminary studies concerning human cachexia, resulting in improved fatigue and quality of life. We present here a review of clinical and experimental evidence regarding the use of carnitine supplementation in the management of cancer cachexia.

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Carnitine--metabolism and functions.

J. Bremer (1983)

Carnitine was detected at the beginning of this century, but it was nearly forgotten among biochemists until its importance in fatty acid metabolism was established 50 years later. In the last 30 years, interest in the metabolism and functions of carnitine has steadily increased. Carnitine is synthesized in most eucaryotic organisms, although a few insects (and most likely some newborn animals) require it as a nutritional factor (vitamin BT). Carnitine biosynthesis is initiated by methylation of lysine. The trimethyllysine formed is subsequently converted to butyrobetaine in all tissues; the butyrobetaine is finally hydroxylated to carnitine in the liver and, in some animals, in the kidneys (see Fig. 1). It is released from these tissues and is then actively taken up by all other tissues. The turnover of carnitine in the body is slow, and the regulation of its synthesis is still incompletely understood. Microorganisms (e.g., in the intestine) can metabolize carnitine to trimethylamine, dehydrocarnitine (beta-keto-gamma-trimethylaminobutyric acid), betaine, and possibly to trimethylaminoacetone. In some insects carnitine can be converted to methylcholine, presumably with trimethylaminoacetone as an intermediate (see Fig. 3). In mammals the unphysiological isomer (+) carnitine is converted to trimethylaminoacetone. The natural isomer (-)carnitine is excreted unchanged in the urine, and it is still uncertain if it is degraded in mammalian tissues at all (Fig. 2). The only firmly established function of carnitine is its function as a carrier of activated fatty acids and activated acetate across the inner mitochondrial membrane. Two acyl-CoA:carnitine acyltransferases with overlapping chain-length specificities have been isolated: one acetyltransferase taking part in the transport of acetyl and short-chain acyl groups and one palmitoyltransferase taking part in the transport of long-chain acyl groups. An additional octanoyltransferase has been isolated from liver peroxisomes. Although a carnitine translocase that allows carnitine and acylcarnitine to penetrate the inner mitochondrial membrane has been deduced from functional studies (see Fig. 5), this translocase has not been isolated as a protein separate from the acyltransferases. Carnitine acetyltransferase and carnitine octanoyltransferase are also found in the peroxisomes. In these organelles the enzymes may be important in the transfer of acyl groups, which are produced by the peroxisomal beta-oxidation enzymes, to the mitochondria for oxidation in the citric acid cycle. The carnitine-dependent transport of activated fatty acids across the mitochondrial membrane is a regulated process. Malonyl-CoA inh

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Oxidative stress and disuse muscle atrophy.

Joseph McClung, Andreas Kavazis, Michelle Powers (2007)

Skeletal muscle inactivity is associated with a loss of muscle protein and reduced force-generating capacity. This disuse-induced muscle atrophy results from both increased proteolysis and decreased protein synthesis. Investigations of the cell signaling pathways that regulate disuse muscle atrophy have increased our understanding of this complex process. Emerging evidence implicates oxidative stress as a key regulator of cell signaling pathways, leading to increased proteolysis and muscle atrophy during periods of prolonged disuse. This review will discuss the role of reactive oxygen species in the regulation of inactivity-induced skeletal muscle atrophy. The specific objectives of this article are to provide an overview of muscle proteases, outline intracellular sources of reactive oxygen species, and summarize the evidence that connects oxidative stress to signaling pathways contributing to disuse muscle atrophy. Moreover, this review will also discuss the specific role that oxidative stress plays in signaling pathways responsible for muscle proteolysis and myonuclear apoptosis and highlight gaps in our knowledge of disuse muscle atrophy. By presenting unresolved issues and suggesting topics for future research, it is hoped that this review will serve as a stimulus for the expansion of knowledge in this exciting field.

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Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer's disease.

D. Butterfield, H. Fai Poon, Daret St. Clair … (2006)

Mild cognitive impairment (MCI) is generally referred to the transitional zone between normal cognitive function and early dementia or clinically probable Alzheimer's disease (AD). Oxidative stress plays a significant role in AD and is increased in the superior/middle temporal gyri of MCI subjects. Because AD involves hippocampal-resident memory dysfunction, we determined protein oxidation and identified the oxidized proteins in the hippocampi of MCI subjects. We found that protein oxidation is significantly increased in the hippocampi of MCI subjects when compared to age- and sex-matched controls. By using redox proteomics, we determined the oxidatively modified proteins in MCI hippocampus to be alpha-enolase (ENO1), glutamine synthetase (GLUL), pyruvate kinase M2 (PKM2) and peptidyl-prolyl cis/trans isomerase 1 (PIN1). The interacteome of these proteins revealed that these proteins functionally interact with SRC, hypoxia-inducible factor 1, plasminogen (PLG), MYC, tissue plasminogen activator (PLAT) and BCL2L1. Moreover, the interacteome indicates the functional involvement of energy metabolism, synaptic plasticity and mitogenesis/proliferation. Therefore, oxidative inactivation of ENO1, GLUL and PIN1 may alter these cellular processes and lead to the development of AD from MCI. We conclude that protein oxidation plays a significant role in the development of AD from MCI and that the oxidative inactivation of ENO1, GLUL, PKM2 and PIN1 is involved in the progression of AD from MCI. The current study provides a framework for future studies on the development of AD from MCI relevant to oxidative stress.

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Author and article information

Contributors

: +55-11-30917225 , +55-11-30917225 , renatasilverio@usp.br

Journal

Journal ID (nlm-ta): J Cachexia Sarcopenia Muscle

Title: Journal of Cachexia, Sarcopenia and Muscle

Publisher: Springer-Verlag (Berlin/Heidelberg )

ISSN (Print): 2190-5991

ISSN (Electronic): 2190-6009

Publication date (Electronic): 26 January 2011

Publication date PMC-release: 26 January 2011

Publication date (Print): March 2011

Volume: 2

Issue: 1

Pages: 37-44

Affiliations

[1 ]Cancer Metabolism Research Group, Institute of Biomedical Sciences, Department of Cell and Developmental Biology, University of São Paulo, Av. Prof. Lineu Prestes, 1524 lab 434, CEP 08800-090 São Paulo, SP Brazil

[2 ]Department of Clinical Medicine, Sapienza University of Rome, Rome, Italy

Article

Publisher ID: 17

DOI: 10.1007/s13539-011-0017-7

PMC ID: 3063878

PubMed ID: 21475677

SO-VID: a6c2b5f9-140d-4097-aa1d-b636fcb67f89

History

Date received : 14 December 2010

Date accepted : 6 January 2011

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ScienceOpen disciplines: Orthopedics

Keywords: cancer,cachexia,l-carnitine,fatigue

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ScienceOpen disciplines: Orthopedics

Keywords: cancer, cachexia, l-carnitine, fatigue

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l-carnitine and cancer cachexia: Clinical and experimental aspects

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Cancer Metabolism

Most cited references 78

Carnitine--metabolism and functions.

Oxidative stress and disuse muscle atrophy.

Redox proteomics identification of oxidatively modified hippocampal proteins in mild cognitive impairment: insights into the development of Alzheimer's disease.

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Cited by 25

Most referenced authors 688