Cachexia occurs in patients with advanced cancers. Despite the adverse clinical impact of cancer-induced muscle wasting, pathways causing cachexia are controversial, and clinically reliable therapies are not available. A trigger of muscle protein loss is the Jak/Stat pathway, and indeed, we found that conditioned medium from C26 colon carcinoma (C26) or Lewis lung carcinoma cells activates Stat3 (p-Stat3) in C2C12 myotubes. We identified two proteolytic pathways that are activated in muscle by p-Stat3; one is activation of caspase-3, and the other is p-Stat3 to myostatin, MAFbx/Atrogin-1, and MuRF-1 via CAAT/enhancer-binding protein δ (C/EBPδ). Using sequential deletions of the caspase-3 promoter and CHIP assays, we determined that Stat3 activation increases caspase-3 expression in C2C12 cells. Caspase-3 expression and proteolytic activity were stimulated by p-Stat3 in muscles of tumor-bearing mice. In mice with cachexia caused by Lewis lung carcinoma or C26 tumors, knock-out of p-Stat3 in muscle or with a small chemical inhibitor of p-Stat3 suppressed muscle mass losses, improved protein synthesis and degradation in muscle, and increased body weight and grip strength. Activation of p-Stat3 stimulates a pathway from C/EBPδ to myostatin and expression of MAFbx/Atrogin-1 and increases the ubiquitin-proteasome system. Indeed, C/EBPδ KO decreases the expression of MAFbx/Atrogin-1 and myostatin, while increasing muscle mass and grip strength. In conclusion, cancer stimulates p-Stat3 in muscle, activating protein loss by stimulating caspase-3, myostatin, and the ubiquitin-proteasome system. These results could lead to novel strategies for preventing cancer-induced muscle wasting.

• Preclinical large animal models play a critical and expanding role in translating basic science findings to the development and clinical approval of novel cardiovascular therapeutics. • This state-of-the-art review outlines existing methodologies and physiological phenotypes of several HF models developed in large animals. A comprehensive list of porcine, ovine, and canine models of disease are presented, and the translational importance of these studies to clinical success is highlighted through a brief overview of recent devices approved by the FDA alongside associated clinical trials and preclinical animal reports. • Increasing the use of large animal models of HF holds significant potential for identifying new mechanisms underlying this disease and providing valuable information regarding the safety and efficacy of new therapies, thus, improving physiological and economical translation of animal research to the successful treatment of human HF.

An increase in intramuscular adipocyte tissue (IMAT) is associated with glucose dysregulation, decreased muscle strength, and increased risk of disability. Unfortunately, the mechanisms stimulating intramuscular adipogenesis remain unclear. We found that dexamethasone (Dex) administration to mice with injured muscles stimulates the accumulation of IMAT. To identify precursors of these adipocytes, we isolated satellite cells and fibro/adipogenic progenitors (FAPs) from muscle; satellite cells did not differentiate into adipocytes even following Dex treatment. In contrast, Dex stimulated FAP differentiation into adipocytes. In vivo , we transplanted purified FAPs from transgenic, EGFP mice into the injured muscles of C57/BL6 mice and found that Dex administration stimulated adipogenesis from FAP‐EGFP. The increase in adipogenesis depended on Dex‐induced inhibition of interleukin‐4 (IL‐4). In the injured muscle of IL‐4‐knockout mice, the levels of adipocytes were increased, while in the injured muscles of Dex‐treated mice with IL‐4 injections, adipogenesis was suppressed. In cultured FAPs, IL‐4 inhibited Dex‐induced conversion of FAPs into adipocytes; this did not occur in FAPs expressing knockdown of the IL‐4 receptor. Thus, we concluded that glucocorticoids stimulate FAPs to differentiate into adipocytes in injured muscles. This process is blocked by IL‐4, suggesting that interfering with IL‐4 signaling could prevent adipogenesis in muscle.—Dong, Y., Silva, K. A. S., Dong, Y., Zhang, L. Glucocorticoids increase adipocytes in muscle by affecting IL‐4 regulated FAP activity. FASEB J. 28, 4123‐4132 (2014). www.fasebj.org

High fructose consumption contributes to metabolic syndrome incidence, whereas exercise training promotes several beneficial adaptations. In this study, we demonstrated the preventive role of exercise training in the metabolic syndrome derangements in a rat model. Wistar rats receiving fructose overload in drinking water (100 g/l) were concomitantly trained on a treadmill (FT) or kept sedentary (F) for 10 wk. Control rats treated with normal water were also submitted to exercise training (CT) or sedentarism (C). Metabolic evaluations consisted of the Lee index and glycemia and insulin tolerance test (kITT). Blood pressure (BP) was directly measured, whereas heart rate (HR) and BP variabilities were evaluated in time and frequency domains. Renal sympathetic nerve activity was also recorded. F rats presented significant alterations compared with all the other groups in insulin resistance (in mg·dl⁻¹·min⁻¹: F: 3.4 ± 0.2; C: 4.7 ± 0.2; CT: 5.0 ± 0.5 FT: 4.6 ± 0.4), mean BP (in mmHG: F: 117 ± 2; C: 100 ± 2; CT: 98 ± 2; FT: 105 ± 2), and Lee index (in g/mm: F = 0.31 ± 0.001; C = 0.29 ± 0.001; CT = 0.27 ± 0.002; FT = 0.28 ± 0.002), confirming the metabolic syndrome diagnosis. Exercise training blunted all these derangements. Additionally, FS group presented autonomic dysfunction in relation to the others, as seen by an ∼50% decrease in baroreflex sensitivity and 24% in HR variability, and increases in sympathovagal balance (140%) and in renal sympathetic nerve activity (45%). These impairments were not observed in FT group, as well as in C and CT. Correlation analysis showed that both Lee index and kITT were associated with vagal impairment caused by fructose. Therefore, exercise training plays a preventive role in both autonomic and hemodynamic alterations related to the excessive fructose consumption.

Endurance exercise begun with reduced muscle glycogen stores seems to potentiate skeletal muscle protein abundance and gene expression. However, it is unknown whether this greater signaling responses is due to performing two exercise sessions in close proximity—as a first exercise session is necessary to reduce the muscle glycogen stores. In the present study, we manipulated the recovery duration between a first muscle glycogen‐depleting exercise and a second exercise session, such that the second exercise session started with reduced muscle glycogen in both approaches but was performed either 2 or 15 hours after the first exercise session (so‐called “twice‐a‐day” and “once‐daily” approaches, respectively). We found that exercise twice‐a‐day increased the nuclear abundance of transcription factor EB (TFEB) and nuclear factor of activated T cells (NFAT) and potentiated the transcription of peroxisome proliferator‐activated receptor‐ɣ coactivator 1‐alpha (PGC‐1α), peroxisome proliferator‐activated receptor‐alpha (PPARα), and peroxisome proliferator‐activated receptor beta/delta (PPARβ/δ) genes, in comparison with the once‐daily exercise. These results suggest that part of the elevated molecular signaling reported with previous “train‐low” approaches might be attributed to performing two exercise sessions in close proximity. The twice‐a‐day approach might be an effective strategy to induce adaptations related to mitochondrial biogenesis and fat oxidation.

The therapeutic potential of mesenchymal stem cells (MSCs) and their conditioned medium (MSC-CM) has been extensively studied. MSCs can repair tissue, reduce local inflammation, and modulate the immune response. Persistent renal tubular interstitial inflammation results in fibrosis and leads to chronic kidney disease (CKD). Unilateral ureteral obstruction (UUO) is a very well-accepted renal fibrosis model. In this study, we evaluated factors influenced by the administration of MSCs or MSC-CM in the UUO model. MSCs extracted from rat bone marrow were cultivated in vitro and characterized by flow cytometry and cellular differentiation. Eight groups of female rats were used in experiments ( n = 7, each), including Sham, UUO, UUO + MSC (obstruction + MSC), and UUO + CM (obstruction + MSC-CM) for 7 days of obstruction and Sham, UUO, UUO + MSC, and UUO + CM for 14 days of obstruction. The MSCs or MSC-CM was administered via the abdominal vena cava after total ligation of the left ureter. After 7 or 14 days, rats were euthanized, and serum and obstructed kidney samples were collected. MSCs or MSC-CM decreased the expression of molecules, such as Collai, α-SMA, and TNF-α. We also observed reductions in the levels of caspase 3, α-SMA, and PCNA in treated animals by immunohistochemistry. Our results suggest that the intravenous administration of MSCs or MSC-CM improves fibrosis progression and factors involved in apoptosis, inflammation, cell proliferation, and epithelial–mesenchymal transition in Wistar rats subjected to UUO, indicating a potential tool for preventing CKD.