Mitochondrial and sarcoplasmic reticulum abnormalities in cancer cachexia: Altered energetic efficiency?

• Published in: Biochimica et biophysica acta 2013-03, Vol.1830 (3), p.2770-2778
• Main Authors: Fontes-Oliveira, Cibely Cristine, Busquets, Sílvia, Toledo, Míriam, Penna, Fabio, Aylwin, Maria Paz, Sirisi, Sònia, Silva, Ana Paula, Orpí, Marcel, García, Albert, Sette, Angelica, Genovese, Maria Inês, Olivan, Mireia, López-Soriano, Francisco J., Argilés, Josep M.
• Format: Article
• Language: English
• Subjects: Adenine Nucleotide Translocator 1 - genetics; Adenine Nucleotide Translocator 1 - metabolism; adenosine triphosphate; Adenosine Triphosphate - deficiency; Animals; ANT1; apoptosis; Apoptosis - genetics; Ca2-transporting ATPase; cachexia; Cachexia - complications; Cachexia - metabolism; Cachexia - pathology; Cancer cachexia; Cell Nucleus - metabolism; Cell Nucleus - ultrastructure; energy efficiency; Energy Metabolism - genetics; F-box proteins; Gene Expression; homeostasis; Male; Mitochondri; mitochondria; Mitochondria - metabolism; Mitochondria - ultrastructure; Muscle Proteins - genetics; Muscle Proteins - metabolism; Muscle wasting; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; muscles; muscular atrophy; Muscular Atrophy - complications; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; Proteolysis; quantitative polymerase chain reaction; Rats; Rats, Wistar; Sarcoma, Yoshida - complications; Sarcoma, Yoshida - metabolism; Sarcoma, Yoshida - pathology; Sarcoplasmic reticulum; Sarcoplasmic Reticulum - metabolism; Sarcoplasmic Reticulum - ultrastructure; Sarcoplasmic Reticulum Calcium-Transporting ATPases - genetics; Sarcoplasmic Reticulum Calcium-Transporting ATPases - metabolism; SERCA; SKP Cullin F-Box Protein Ligases - genetics; SKP Cullin F-Box Protein Ligases - metabolism; transmission electron microscopy; Tripartite Motif Proteins; ubiquitin-protein ligase; Ubiquitin-Protein Ligases - genetics; Ubiquitin-Protein Ligases - metabolism; Western blotting
• ISSN: 0304-4165; 0006-3002; 1872-8006
• DOI: 10.1016/j.bbagen.2012.11.009

Cachexia is a wasting condition that manifests in several types of cancer, and the main characteristic is the profound loss of muscle mass. The Yoshida AH-130 tumor model has been used and the samples have been analyzed using transmission electronic microscopy, real-time PCR and Western blot techniques. Using in vivo cancer cachectic model in rats, here we show that skeletal muscle loss is accompanied by fiber morphologic alterations such as mitochondrial disruption, dilatation of sarcoplasmic reticulum and apoptotic nuclei. Analyzing the expression of some factors related to proteolytic and thermogenic processes, we observed in tumor-bearing animals an increased expression of genes involved in proteolysis such as ubiquitin ligases Muscle Ring Finger 1 (MuRF-1) and Muscle Atrophy F-box protein (MAFBx). Moreover, an overexpression of both sarco/endoplasmic Ca2+-ATPase (SERCA1) and adenine nucleotide translocator (ANT1), both factors related to cellular energetic efficiency, was observed. Tumor burden also leads to a marked decreased in muscle ATP content. In addition to muscle proteolysis, other ATP-related pathways may have a key role in muscle wasting, both directly by increasing energetic inefficiency, and indirectly, by affecting the sarcoplasmic reticulum–mitochondrial assembly that is essential for muscle function and homeostasis. The present study reports profound morphological changes in cancer cachectic muscle, which are visualized mainly in alterations in sarcoplasmic reticulum and mitochondria. These alterations are linked to pathways that can account for energy inefficiency associated with cancer cachexia. ► Skeletal muscle from cachectic animals showed fiber morphologic alterations. ► These alterations are mitochondrial disruption and dilatation of sarcoplasmic reticulum. ► An overexpression of both sarco/endoplasmic Ca2+-ATPase (SERCA1) and adenine nucleotide translocator (ANT1) was reported. ► Tumor burden also leads to a marked decreased in muscle ATP content.