sirolimus and Cachexia

Recent studies have correlated physical activity with a better prognosis in cachectic patients, although the underlying mechanisms are not yet understood. In order to identify the pathways involved in the physical activity-mediated rescue of skeletal muscle mass and function, we investigated the effects of voluntary exercise on cachexia in colon carcinoma (C26)-bearing mice. Voluntary exercise prevented loss of muscle mass and function, ultimately increasing survival of C26-bearing mice. We found that the autophagic flux is overloaded in skeletal muscle of both colon carcinoma murine models and patients, but not in running C26-bearing mice, thus suggesting that exercise may release the autophagic flux and ultimately rescue muscle homeostasis. Treatment of C26-bearing mice with either AICAR or rapamycin, two drugs that trigger the autophagic flux, also rescued muscle mass and prevented atrogene induction. Similar effects were reproduced on myotubes in vitro, which displayed atrophy following exposure to C26-conditioned medium, a phenomenon that was rescued by AICAR or rapamycin treatment and relies on autophagosome-lysosome fusion (inhibited by chloroquine). Since AICAR, rapamycin and exercise equally affect the autophagic system and counteract cachexia, we believe autophagy-triggering drugs may be exploited to treat cachexia in conditions in which exercise cannot be prescribed.

Topics: Aminoimidazole Carboxamide; Animals; Autophagosomes; Autophagy; Cachexia; Cell Line, Tumor; Colonic Neoplasms; Female; Humans; Lysosomes; Mice; Mice, Inbred BALB C; Muscle Fibers, Skeletal; Muscle Weakness; Muscle, Skeletal; Neoplasm Transplantation; Physical Conditioning, Animal; Ribonucleotides; Sirolimus; Survival Analysis

Anorexia-cachexia syndrome (ACS) is a major determinant of cancer-related death that causes progressive body weight loss due to depletion of skeletal muscle mass and body fat. Here, we report the development of a novel preclinical murine model of ACS in which lymphomas harbor elevated Myc and activated mTOR signaling. The ACS phenotype in this model correlated with deregulated expression of a number of cytokines, including elevated levels of interleukin-10 which was under the direct translational control of mTOR. Notably, pharmacologic intervention to impair protein synthesis restored cytokine production to near-normal levels, delayed ACS progression, and extended host survival. Together, our findings suggest a new paradigm to treat ACS by strategies which target protein synthesis to block the production of procachexic factors.

Topics: Animals; Anorexia; Antineoplastic Agents; Body Weight; Cachexia; Cell Line, Tumor; Colonic Neoplasms; Disease Models, Animal; Female; Harringtonines; Homoharringtonine; Humans; Interleukin-10; Kaplan-Meier Estimate; Lymphoma; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Protein Biosynthesis; Proto-Oncogene Proteins c-myc; Signal Transduction; Sirolimus; Syndrome; TOR Serine-Threonine Kinases

Although ghrelin and GHRP-2 have been shown to inhibit skeletal muscle proteolysis in rats with burn injury, the effects of des-acyl ghrelin (DAG) have not been reported. In this paper, we demonstrate that continuous 24h administration of DAG attenuated burn-induced EDL muscle proteolysis, and normalized elevated TNFα mRNA. Combined treatment of cultured C2C12 myotubes with TNFα and IFN-γ (TNF+IFN) inhibited protein synthesis and increased protein breakdown; DAG abolished both effects. PI3 kinase inhibition by LY294002 and mTOR inhibition by rapamycin blocked the reversal of the anti-anabolic effects of TNF+IFN-treated myotubes by DAG. DAG also reversed or attenuated the TNF+IFN-induced reduction in phosphorylation of Akt, FOXO1, 4E-BP-1, and GSK-3β in myotubes. Furthermore, DAG attenuated the atrophy signal, phospho-NF-κB, and the mRNA expression of MAFbx and MuRF1, upregulated by TNF+IFN in C2C12 myotubes. We conclude that DAG reduces muscle cachexia produced by injury and proinflammatory cytokines, and that DAG or DAG-based compounds may be useful in treating wasting disorders.

Topics: Anabolic Agents; Animals; Burns; Cachexia; Carrier Proteins; Cells, Cultured; Chromones; Forkhead Transcription Factors; Ghrelin; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Interferon-gamma; Intracellular Signaling Peptides and Proteins; Mice; Morpholines; Muscle Fibers, Skeletal; Muscle Proteins; Muscle, Skeletal; Nerve Tissue Proteins; NF-kappa B; Phosphoinositide-3 Kinase Inhibitors; Phosphoproteins; Phosphorylation; Protein Biosynthesis; Proteolysis; Proto-Oncogene Proteins c-akt; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sirolimus; SKP Cullin F-Box Protein Ligases; TOR Serine-Threonine Kinases; Tripartite Motif Proteins; Tumor Necrosis Factor-alpha; Ubiquitin-Protein Ligases