The Role of Cytokines in Muscle Wasting: Its Relation with Cancer Cachexia Josep M. Argiles,* Celia Garcia-Martinez, Marta Llovera, and Francisco J. Lopez-Soriano Departament de Bioquimica i Fisiologia, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain Introduction .................................................................. I. Amino Acid Metabolism in the Tumor-Bearing Host ..................... 11. Protein Turnover in Skeletal Muscle .................................... 111. The Role of Cytokines ................................................ IV. TNF and Cancer Cachexia V. Concluding Remarks .... Acknowledgm References ... 637 637 640 641 646 648 649 649 INTRODUCTION Malignant growth induces-in an experimental animal or patient-a pro- gressive net loss of lean body mass, which predisposes it to an increased risk of morbidity in the acute phase. Furthermore, depletion of muscle mass can prolong rehabilitation to normal physiological function following recovery. Understanding the nature of the protein catabolic response to tumor growth is thus important from the therapeutic standpoint. In addition, it provides an excellent model for a better understanding of the regulation of protein syn- thesis and breakdown in skeletal muscle. Unfortunately, the nature of changes in protein and amino acid metabolism in cancer-bearing states in both experimental animals and human subjects have not yet been clearly eluci- dated. The recent discovery of a series of macrophage-derived factors- cytokines-has opened new perspectives in the understanding of nitrogen wastage associated with cancer cachexia. It is the aim of the present review to update all the information concerning the effects of cytokines on muscle wasting and to relate them to the development of cachexia. I. AMINO ACID METABOLISM IN THE TUMOR-BEARING HOST In 1951, Miderl described a tumor as a nitrogen trap, this term indicating the ability of a tumor to act as a nitrogen sink where amino acids are retained and used for both oxidation and nucleic acid and protein synthesis. Certain amino acids are essential for tumor growth in some cancer-bearing states. This is the case of asparagine, which is essential for the growth of certain tumors 2,3-in *Address for correspondence: Unitat de Bioquimica i Biologia Molecular B, Departament de Bioquimica i Fisiologia, Facultat de Biologia, Universitat de Barcelona, Diagonal 645, 08071-Bar- celona, Spain Medicinal Research Reviews, Vol. 12, No. 6, 637-652 (1992) 0 1992 John Wiley & Sons, Inc. CCC 0198-6325/92/060637-16