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Cachexia is frequently accompanied by severe metabolic derangements, although the mechanisms responsible for this debilitating condition remain unclear. Pyruvate dehydrogenase kinase (PDK)4, a critical regulator of cellular energetic metabolism, was found elevated in experimental models of cancer, starvation, diabetes, and sepsis. Here we aimed to investigate the link between PDK4 and the changes in muscle size in cancer cachexia. High PDK4 and abnormal energetic metabolism were found in the skeletal muscle of colon-26 tumor hosts, as well as in mice fed a diet enriched in Pirinixic acid, previously shown to increase PDK4 levels. Viral-mediated PDK4 overexpression in myotube cultures was sufficient to promote myofiber shrinkage, consistent with enhanced protein catabolism and mitochondrial abnormalities. On the contrary, blockade of PDK4 was sufficient to restore myotube size in C2C12 cultures exposed to tumor media. Our data support, for the first time, a direct role for PDK4 in promoting cancer-associated muscle metabolic alterations and skeletal muscle atrophy. [ABSTRACT FROM AUTHOR]

Muscle wasting in cancer is associated with deficits in protein synthesis, yet, the mechanisms underlying this anabolic impairment remain poorly understood. The capacity for protein synthesis is mainly determined by the abundance of muscle ribosomes, which is in turn regulated by transcription of the ribosomal (r)RNA genes (rDNA). In this study, we investigated whether muscle loss in a preclinical model of ovarian cancer is associated with a reduction in ribosomal capacity and was a consequence of impaired rDNA transcription. Tumor bearing resulted in a significant loss in gastrocnemius muscle weight and protein synthesis capacity, and was consistent with a significant reduction in rDNA transcription and ribosomal capacity. Despite the induction of the ribophagy receptor NUFIP1 mRNA and the loss of NUFIP1 protein, in vitro studies revealed that while inhibition of autophagy rescued NUFIP1, it did not prevent the loss of rRNA. Electrophoretic analysis of rRNA fragmentation from both in vivo and in vitro models showed no evidence of endonucleolytic cleavage, suggesting that rRNA degradation may not play a major role in modulating muscle ribosome abundance. Our results indicate that in this model of ovarian cancer‐induced cachexia, the ability of skeletal muscle to synthesize protein is compromised by a reduction in rDNA transcription and consequently a lower ribosomal capacity. Thus, impaired ribosomal production appears to play a key role in the anabolic deficits associated with muscle wasting in cancer cachexia. [ABSTRACT FROM AUTHOR]

L7888 --> 959.5 --> Colorectal cancer (CRC) is the second deadliest cancer in the United States, with ~70% of CRC cases developing liver metastases and cachexia. Here we investigated two tumor types (HCT116 and C26) as xenograft (x) or metastatic (m) models. Male Nod SCID gamma and CD2F1 mice were injected subcutaneously or intrasplenically with HCT116 or C26 tumor cells, respectively. CRC tumor growth was investigated at 30 days (xHCT116), 24 days (mHCT116), and 14 days (xC26 and mC26), and resulted in a significant gastrocnemius muscle depletion regardless of tumor model or type (xHCT116: 14.2%, mHCT116: 29.0%, xC26: 20.4%, mC26: 17.1%; P < 0.05). mHCT116 tumors caused a reduction in ribosomal (r)RNA content (21.2%, P < 0.05) and rDNA transcription (40%, P < 0.001), but the mC26 tumor showed no loss of rRNA and the upregulation of rDNA transcription (>2‐fold, P < 0.001). All tumor‐bearing mice experienced a reduction in γ4E‐BP1 phosphorylation (xHCT116: 57.8%, mHCT116: 73.4%, xC26: 50.9%, mC26: 99.2%; P < 0.05) suggesting impaired translational control. Muscle IL‐6 mRNA was elevated in all tumor‐bearing mice except xHCT116 (mHCT116: 1.8‐fold, xC26: 3.6‐fold, mC26: 4.1‐fold; P < 0.05). TNF‐α mRNA was lower in xHCT116 (52.9%, P < 0.05) and was not induced in the other tumor‐bearing mice. Expression of the NOD‐, LRR‐ and pyrin domain‐containing protein 3 (NLRP3) was elevated only in mC26 muscle (5‐fold, P < 0.0001). Neither IL‐18 nor IL‐1β mRNA levels were consistent with changes in NLRP3, however IL‐1β mRNA increased in both tumor models and types (xHCT116: 5.5‐fold, mHCT116: 10‐fold, xC26: 2.5‐fold, mC26: 3.5‐fold; P < 0.05) with a greater expression in each metastatic relative to the xenograft model within each type of tumor. Our findings indicate that the mHCT116 tumor results in more drastic muscle depletion and anabolic deficits, while the mC26 exhibited a divergent pro‐inflammatory phenotype than the xenograft model. Our data highlight potentially important divergence in the pathogenesis of muscle wasting among the HCT116 and C26 pre‐clinical models of CRC. [ABSTRACT FROM AUTHOR]

Cancer cachexia is a multifactorial syndrome characterized by anorexia, body wasting, and muscle and adipose tissue loss, impairing patient's tolerance to anticancer treatments and survival. The aim of the present study was to compare the effects induced in mice by tumor growth alone (C26) or in combination with chemotherapy [C26 oxaliplatin and 5-fluorouracil (oxfu)] and to evaluate the potential of moderate exercise. Oxfu administration to C26 mice exacerbated muscle wasting and triggered autophagy or mitophagy, decreased protein synthesis, and induced mitochondrial alterations. Exercise in C26 oxfu mice counteracted the loss of muscle mass and strength, partially rescuing autophagy and mitochondrial function. Nevertheless, exercise worsened survival in C26 oxfu mice in late stages of cachexia. In summary, chemotherapy further impinges on cancer-induced alterations, worsening muscle wasting. An ideal multifactorial and early intervention to prevent cancer cachexia could take advantage of exercise, improving patient's energy metabolism, mobility, and quality of life. [ABSTRACT FROM AUTHOR]