Background:No reliable treatment exists for cancer-related muscle loss. Results: In muscles of mice with cancer, p-Stat3 stimulates proteolysis by activating caspase-3 and the ubiquitin-proteasome system through a C/EBP␦ and myostatin pathway. Conclusion: Inhibition of Stat3 suppresses cancer-induced muscle losses.Significance: A small-molecule Stat3 inhibitor could be integrated into therapeutic strategies for preventing cancer-induced muscle losses.

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.

Moraes-Silva IC, Mostarda C, Moreira ED, Silva KAS, dos Santos F, de Angelis K, Farah VMA V, Irigoyen MC. Preventive role of exercise training in autonomic, hemodynamic, and metabolic parameters in rats under high risk of metabolic syndrome development. J Appl Physiol 114: 786 -791, 2013. First published January 17, 2013 doi:10.1152/japplphysiol.00586.2012.-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 Ϫ1 ·min Ϫ1 : F: 3.4 Ϯ 0.2; C: 4.7 Ϯ 0.2; CT: 5.0 Ϯ 0.5 FT: 4.6 Ϯ 0.4), mean BP (in mmHG: F: 117 Ϯ 2; C: 100 Ϯ 2; CT: 98 Ϯ 2; FT: 105 Ϯ 2), and Lee index (in g/mm: F ϭ 0.31 Ϯ 0.001; C ϭ 0.29 Ϯ 0.001; CT ϭ 0.27 Ϯ 0.002; FT ϭ 0.28 Ϯ 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 ϳ50% 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.fructose; exercise training; autonomic nervous system SEVERAL STUDIES HAVE SHOWN that poor eating habits and a large increase in fructose consumption in recent years has contributed to the epidemic of metabolic syndrome (2, 5). These unhealthy habits may result in physiological changes that contribute to a higher morbidity and mortality in humans (14). Among these changes, increase of blood pressure, plasma lipids, obesity, glucose intolerance, insulin resistance, and hyperinsulinemia are the most evident. Additionally, studies have shown an association between these factors as hyperinsulinemia and hypertension, in both humans and animals (10, 21, 36), indicating that once these alterations are present, the higher is the incidence of cardiovascular diseases.Autonomic nervous system dysfunction also accompanies these metabolic disturbances. Our research group has ...

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.

In catabolic conditions such as aging and diabetes, IGF signaling is impaired and fibrosis develops in skeletal muscles. To examine whether impaired IGF signaling initiates muscle fibrosis, we generated IGF-IR(+/-) heterozygous mice by crossing loxP-floxed IGF-IR (exon 3) mice with MyoD-cre mice. IGF-IR(+/-) mice were studied because we were unable to obtain homozygous IGF-IR-KO mice. In IGF-IR(+/-) mice, both growth and expression of myogenic genes (MyoD and myogenin; markers of satellite cell proliferation and differentiation, respectively) were depressed. Likewise, in injured muscles of IGF-IR(+/-) mice, there was impaired regeneration, depressed expression of MyoD and myogenin, and increased expression of TGF-β1, α-SMA, collagen I, and fibrosis. To uncover mechanisms stimulating fibrosis, we isolated satellite cells from muscles of IGF-IR(+/-) mice and found reduced proliferation and differentiation plus increased TGF-β1 production. In C2C12 myoblasts (a model of satellite cells), IGF-I treatment inhibited TGF-β1-stimulated Smad3 phosphorylation, its nuclear translocation, and expression of fibronectin. Using immunoprecipitation assay, we found an interaction between p-Akt or Akt with Smad3 in wild-type mouse muscles and in C2C12 myoblasts; importantly, IGF-I increased p-Akt and Smad3 interaction, whereas TGF-β1 decreased it. Therefore, in muscles of IGF-IR(+/-) mice, the reduction in IGF-IR reduces p-Akt, allowing for dissociation and nuclear translocation of Smad3 to enhance the TGF-β1 signaling pathway, leading to fibrosis. Thus, strategies to improve IGF signaling could prevent fibrosis in catabolic conditions with impaired IGF signaling.

BackgroundThe effects of streptozotocin (STZ)-induced diabetes on heart metabolism and function after myocardial infarction (MI) remodelling were investigated in rats.MethodsFifteen days after STZ (50 mg/kg b.w. i.v.) injection, MI was induced by surgical occlusion of the left coronary artery. Two weeks after MI induction, contents of glycogen, ATP, free fatty acids and triacylglycerols (TG) and enzyme activities of glycolysis and Krebs cycle (hexokinase, glucose-6-phosphate dehydrogenase, phosphofructokinase, citrate synthase) and expression of carnitine palmitoyl-CoA transferase I (a key enzyme of mitochondrial fatty acid oxidation) were measured in the left ventricle (LV). Plasma glucose, free fatty acids and triacylglycerol levels were determined. Ejection fraction (EF) and shortening fraction (SF) were also measured by echocardiography.ResultsGlycogen and TG contents were increased (p < 0.05) whereas ATP content was decreased in the LV of the non-infarcted diabetic group when compared to the control group (p < 0.05). When compared to infarcted control rats (MI), the diabetic infarcted rats (DI) showed (p < 0.05): increased plasma glucose and TG levels, elevated free fatty acid levels and increased activity of, citrate synthase and decreased ATP levels in the LV. Infarct size was smaller in the DI group when compared to MI rats (p < 0.05), and this was associated with higher EF and SF (p < 0.05).ConclusionsSystolic function was preserved or recovered more efficiently in the heart from diabetic rats two weeks after MI, possibly due to the high provision of glucose and free fatty acids from both plasma and heart glycogen and triacylglycerol stores.

Angiotensin II (ANG II)-induced skeletal muscle wasting is characterized by activation of the ubiquitin-proteasome system. However, the potential involvement of proteolytic system macroautophagy/autophagy in this wasting process remains elusive. Autophagy is precisely regulated to maintain cell survival and homeostasis; thus its dysregulation (i.e., overactivation or persistent suppression) could lead to detrimental outcomes in skeletal muscle. Here we show that infusion of ANG II for 7 days in male FVB mice suppressed autophagy in skeletal muscle. ANG II blunted microtubule-associated protein 1 light chain 3B (LC3B)-I-to-LC3B-II conversion (an autophagosome marker), increased p62/SQSTM1 (an autophagy cargo receptor) protein expression, and decreased the number of autophagic vacuoles. ANG II inhibited UNC-51-like kinase 1 via inhibition of 5′-AMP-activated kinase and activation of mechanistic target of rapamycin complex 1, leading to reduced phosphorylation of beclin-1Ser14 and Autophagy-related protein 14Ser29, suggesting that ANG II impairs autophagosome formation in skeletal muscle. In line with ANG II-mediated suppression of autophagy, ANG II promoted accumulation of abnormal/damaged mitochondria, characterized by swelling and disorganized cristae and matrix dissolution, with associated increase in PTEN-induced kinase 1 protein expression. ANG II also reduced mitochondrial respiration, indicative of mitochondrial dysfunction. Together, these results demonstrate that ANG II reduces autophagic activity and disrupts mitochondrial ultrastructure and function, likely contributing to skeletal muscle wasting. Therefore, strategies that activate autophagy in skeletal muscle have the potential to prevent or blunt ANG II-induced skeletal muscle wasting in chronic diseases. NEW & NOTEWORTHY Our study identified a novel mechanism whereby angiotensin II (ANG II) impairs mitochondrial energy metabolism in skeletal muscle. ANG II suppressed autophagosome formation by inhibiting the UNC-51-like kinase 1(ULK1)-beclin-1 axis, resulting in accumulation of abnormal/damaged and dysfunctional mitochondria and reduced mitochondrial respiratory capacity. Therapeutic strategies that activate the ULK1-beclin-1 axis have the potential to delay or reverse skeletal muscle wasting in chronic diseases characterized by increased systemic ANG II levels.

Highlights 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.