Apoptosis is present in skeletal muscle of cachectic gastro-intestinal cancer patients

doi:10.1016/j.clnu.2007.06.005

Clinical Nutrition

Volume 26, Issue 5, October 2007, Pages 614-618

https://doi.org/10.1016/j.clnu.2007.06.005 Get rights and content

Summary

Background & aims

Previous studies of our research group have shown that apoptosis is present in skeletal muscle of tumour-bearing animals subject to cachexia. For this reason we decided to investigate the apoptosis in skeletal muscle of cancer patients.

Methods and results

In the present study, muscle biopsies from weight-losing patients with upper gastro-intestinal cancer showed a significant increase in muscle DNA fragmentation (three-fold), as compared with control subjects. The increase in DNA laddering was associated with an increase in poly(ADP-ribose) polymerase (PARP) cleavage (four-fold) as measured by western blotting. These two events indicate the presence of muscle apoptosis. These changes were associated with a decrease in MyoD protein content, suggesting important alterations in skeletal muscle physiology.

Conclusions

The results presented therefore confirm that apoptosis is also present in human subjects undergoing cancer cachexia.

Introduction

Perhaps the most common manifestation of advanced malignant disease is the development of cancer cachexia. Indeed, cachexia occurs in the majority of cancer patients before death, and accordingly to Warren¹ it is responsible for the death of 22% of cancer patients, although lower percentages have been considered in more recent publications.² The abnormalities associated with cancer cachexia include anorexia, weight loss, muscle loss, skeletal muscle atrophy, anaemia and alterations in carbohydrate, lipid and protein metabolism.³ The degree of cachexia is inversely correlated with the survival time of the patient and it always implies a poor prognosis.4, 5, 6 Perhaps one of the most relevant characteristics of cachexia is that of asthenia, which reflects the extensive muscle waste that takes place in the cachectic cancer patient.⁷ Asthenia is also characterized by a general weakness as well as physical and mental fatigue.⁸ Actually, body protein depletion is one of the main trends of cachexia and it involves not only skeletal muscle but it also affects cardiac proteins, resulting in alterations in heart performance.

Previous studies from our laboratory have shown that, together with myofibrillar protein loss, skeletal muscle of cachectic tumour-bearing animals is subject to an important activation of DNA fragmentation, and therefore, apoptosis.⁹ Apoptotic cell death is characterized by a common pattern of morphological alterations such as chromatin condensation, membrane blebbing, DNA fragmentation and cell shrinkage.¹⁰ Interestingly, our group has shown that different anticachectic treatments result not only in a restauration of skeletal muscle protein content, but also in an amelioration of apoptosis.11, 12 For instance, formoterol (a β₂-adrenergic agent) treatment to tumour-bearing animals results in a dramatic reduction of DNA fragmentation in skeletal muscle.¹² Unfortunately, no reports describing skeletal muscle apoptosis in humans have been published. Bearing this in mind, the object of the present investigation was to study the apoptotic phenomenon in muscle biopsies from cancer patients.

Section snippets

Patients and controls

Patients diagnosed with oesophageal, gastric or pancreatic cancer within the Lothian and Border regions between February 1999 and March 2004 were eligible for inclusion into the study. Patients were recruited at the time of diagnosis and all subjects provided written informed consent and the study received ethical permission from the Lothian Research Ethics Committee. Patients not suitable for surgical resection (advanced disease stage or co-morbidity) were excluded from the study. In addition,

Results

The main clinical characteristics of the chosen patients are pictured in Table 1. A clear inflammatory status was present as observed by a clear tendency for an elevation of the acute-phase reactant CRP (50%) together with a significant decrease in albumin (10%) (Table 1). Concerning cytokine levels, the patients showed a tendency for higher circulating IL-6 and sTNFR2 levels but the differences did not reach statistical significance. The patients also showed a tendency for lower levels of

Discussion

Until now no data concerning muscle apoptosis in humans undergoing cancer have been published. For this reason, in this study we chose upper gastro-intestinal cancer patients suffering an average weight loss of 5% in 1 month.

In order to examine the apoptotic phenomenon in skeletal muscle of these patients, needle muscle biopsies were performed, and the samples were used for both DNA fragmentation analysis and PPAR cleavage testing. The reason why we used two different techniques to assess

Acknowledgements

This work was supported by grants from the Dirección General de Investigación Científica y Técnica (SAF4744-2005) of the Ministerio de Educación y Ciencia, from the Generalitat de Catalunya (SGR/00108), from Ministerio de Ciencia y Tecnologia (VIN03/021) and by Grants SAF-2003-04223 and SAF4744-2005 from the Ministerio de Ciencia y Tecnología (MCyT). Sílvia Busquets, Chris Deans and Rodrigo Moore-Carrasco contributed with the design of the experiment; Sílvia Busquets, Maite Figueras, Francisco

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ORIGINAL ARTICLEApoptosis is present in skeletal muscle of cachectic gastro-intestinal cancer patients

Summary

Background & aims

Methods and results

Conclusions

Introduction

Section snippets

Patients and controls

Results

Discussion

Acknowledgements

Biochem Biophys Res Commun

FEBS Lett

Anal Biochem

Int J Biochem Cell Biol

The immediate cause of death in cancer

Am J Med Sci

Effects of cachexia due to cancer on whole body and skeletal muscle protein turnover

Cancer

The metabolic basis of cancer cachexia

Med Res Rev

Nutritional assessment and patient outcome during oncological therapy

Cancer

Protein-caloric undernutrition in hospitalized cancer patients

Am J Med

Management of cancer cachexia

Semin Oncol

The role of cytokines in muscle wasting: its relation with cancer cachexia

Med Res Rev

ORIGINAL ARTICLE
Apoptosis is present in skeletal muscle of cachectic gastro-intestinal cancer patients