In lung cancer, muscular NF-κB activity is induced by factors contained within the circulation. Autophagy may contribute to increased muscle proteolysis in lung cancer cachexia, whereas the absence of downstream changes in phosphosubstrates despite increased Akt phosphorylation suggests impaired anabolic signaling that may require targeted nutritional intervention.

The calcium-activated phosphatase calcineurin has been implicated as a critical intracellular signal transducer of cardiomyocyte hypertrophy. Although previous data suggested the nuclear factor of activated T-cells (NFAT) as its sole transcriptional effector, the absolute requirement of NFAT as a mediator of calcineurin signaling has not been examined in the heart. We therefore investigated the expression and activation profile of NFAT genes in the heart. Four members (NFATc1-c4) are expressed in cardiomyocytes, elicit nuclear translocation upon calcineurin activation, and are able to drive transactivation of cardiac promoter luciferase constructs. To define the necessary function of NFAT factors as hypertrophic transducers, a dominant negative NFAT construct was created, encompassing part of the N-terminal region of NFATc4 containing a conserved calcineurin-binding motif. Cotransfection of this construct dose-dependently abrogated promoter activation, irrespective of the NFAT isoform used, whereas a control construct with the calcineurin-binding motif mutated displayed no such effects. Adenoviral gene transfer of dominant negative NFAT rendered cardiomyocytes resistant toward all aspects of calcineurin or agonist-induced cardiomyocyte hypertrophy, whereas adenoviral gene transfer of the control construct had no discernable effect on these parameters. These results indicate that multiple NFAT isoforms are expressed in cardiomyocytes where they function as necessary transducers of calcineurin in facilitating cardiomyocyte hypertrophy.Heart failure is a leading cause of morbidity and mortality in industrial countries, affecting over 10 million Americans and Western Europeans, with a 5-year mortality approaching 50% despite current medical therapy (1).1 These mortality figures reflect the lack of biologically efficacious therapies directed against the underlying disease processes that lead to maladaptive left ventricular remodeling and, ultimately, failure itself. In response to a plethora of intra-and extracardiac stimuli, cardiomyocytes exhibit cellular enlargement or hypertrophy as a compensatory adaptation to increased ventricular wall stress (3). However, sustained cardiac hypertrophy is the single most important risk factor for the development of heart failure (4, 5). Because intracellular signaling pathways are thought to both initiate and perpetuate the cardiac hypertrophic response and its transition to dilated failure, recent investigation has attempted the identification of key regulatory factors with the goal of defining novel therapeutic targets (3).One recently characterized intracellular signaling pathway that links extracellular stimuli to a hypertrophic transcriptional response employs the phosphatase calcineurin and its downstream transcriptional effector nuclear factor of activated T-cells (NFAT).2 Four of the five NFAT proteins (NFATc1, NFAT2, or NFATc; NFATc2, NFAT1, or NFATp; NFATc3, NFAT4, or NFATx; and NFATc4 or NFAT3) reside in the cytoplasm in unstimulated cells but quickly translocate to ...

Muscle wasting impairs physical performance, increases mortality and reduces medical intervention efficacy in chronic diseases and cancer. Developing proficient intervention strategies requires improved understanding of the molecular mechanisms governing muscle mass wasting and recovery. Involvement of muscle protein- and myonuclear turnover during recovery from muscle atrophy has received limited attention. The insulin-like growth factor (IGF)-I signaling pathway has been implicated in muscle mass regulation. As glycogen synthase kinase 3 (GSK-3) is inhibited by IGF-I signaling, we hypothesized that muscle-specific GSK-3β deletion facilitates the recovery of disuse-atrophied skeletal muscle. Wild-type mice and mice lacking muscle GSK-3β (MGSK-3β KO) were subjected to a hindlimb suspension model of reversible disuse-induced muscle atrophy and followed during recovery. Indices of muscle mass, protein synthesis and proteolysis, and post-natal myogenesis which contribute to myonuclear accretion, were monitored during the reloading of atrophied muscle. Early muscle mass recovery occurred more rapidly in MGSK-3β KO muscle. Reloading-associated changes in muscle protein turnover were not affected by GSK-3β ablation. However, coherent effects were observed in the extent and kinetics of satellite cell activation, proliferation and myogenic differentiation observed during reloading, suggestive of increased myonuclear accretion in regenerating skeletal muscle lacking GSK-3β. This study demonstrates that muscle mass recovery and post-natal myogenesis from disuse-atrophy are accelerated in the absence of GSK-3β.

Cloots RH, Sankaranarayanan S, de Theije CC, Poynter ME, Terwindt E, van Dijk P, Hakvoort TB, Lamers WH, Köhler SE. Ablation of Arg1 in hematopoietic cells improves respiratory function of lung parenchyma, but not that of larger airways or inflammation in asthmatic mice. Am J Physiol Lung Cell Mol Physiol 305: L364-L376, 2013. First published July 5, 2013; doi:10.1152/ajplung.00341.2012.-Asthma is a chronic inflammatory disease of the small airways, with airway hyperresponsiveness (AHR) and inflammation as hallmarks. Recent studies suggest a role for arginase in asthma pathogenesis, possibly because arginine is the substrate for both arginase and NO synthase and because NO modulates bronchial tone and inflammation. Our objective was to investigate the importance of increased pulmonary arginase 1 expression on methacholine-induced AHR and lung inflammation in a mouse model of allergic asthma. Arginase 1 expression in the lung was ablated by crossing Arg1 fl/fl with Tie2Cre tg/Ϫ mice. Mice were sensitized and then challenged with ovalbumin. Lung function was measured with the Flexivent. Adaptive changes in gene expression, chemokine and cytokine secretion, and lung histology were quantified with quantitative PCR, ELISA, and immunohistochemistry. Arg1 deficiency did not affect the allergic response in lungs and large-airway resistance, but it improved peripheral lung function (tissue elastance and resistance) and attenuated adaptive increases in mRNA expression of arginine-catabolizing enzymes Arg2 and Nos2, arginine transporters Slc7a1 and Slc7a7, chemokines Ccl2 and Ccl11, cytokines Tnfa and Ifng, mucus-associated epithelial markers Clca3 and Muc5ac, and lung content of IL-13 and CCL11. However, expression of Il4, Il5, Il10, and Il13 mRNA; lung content of IL-4, IL-5, IL-10, TNF-␣, and IFN-␥ protein; and lung pathology were not affected. Correlation analysis showed that Arg1 ablation disturbed the coordinated pulmonary response to ovalbumin challenges, suggesting arginine (metabolite) dependence of this response. Arg1 ablation in the lung improved peripheral lung function and affected arginine metabolism but had little effect on airway inflammation. airway hyperresponsiveness; arginine; inflammation ALLERGIC ASTHMA IS A CHRONIC inflammatory disorder of the lung that is characterized by a reversible limitation of the airflow due to an allergic reaction in the airways with the characteristics of a T H 2-predominant airway inflammation. The airway inflammation is initiated by the binding of inhaled allergens to complementary IgEs on IgE receptor-bearing cells. Upon activation, these cells release histamine, cytokines, and proteases, resulting in the activation of the inflammatory cascade with lung infiltration of eosinophils and mononuclear cells. Increased mucus production, mucosal edema, and a disproportionate smooth-muscle contraction lead to airway hyperresponsiveness (AHR). As a result of the recurring inflammation, airway remodeling develops as a consequence of fibrosis and airway wall thickening (2,3,6,36).Rec...

Together with elevated myogenic signaling, the increase in muscle protein turnover signaling in COPD, which is even more prominent in COPD patients with sarcopenia, reflects molecular alterations associated with muscle repair and remodeling.