trichostatin-a and Muscular-Atrophy

It is well known that cigarette smoke (CS) is the main risk factor for chronic obstructive pulmonary disease (COPD) accompanied by skeletal muscle atrophy. Histone deacetylases (HDACs) that remove acetyl groups from target proteins are necessary for the muscle atrophy associated with skeletal muscle disuse. However, the role of HDACs and trichostatin A (TSA), a HDAC inhibitor, in skeletal muscle atrophy caused by CS exposure remains poorly understood.. Female mice were exposed to CS twice daily for 40 days and TSA injected intraperitoneally into CS-exposed mice on alternate days. Skeletal muscles were weighed and gastrocnemius (Gas) muscle histomorphology examined by hematoxylin and eosin staining. Histone deacetylases 1 and 2 (HDAC1/2), and markers of ubiquitin degradation, muscle differentiation, apoptosis, pyroptosis, and the cytoskeletal proteins were assessed by western blot and immunohistochemistry in Gas.. CS exposure decreased body and skeletal muscle weights and triggered an increase in the percentage of fiber with centralized nuclei in Gas. HDAC1/2 proteins were upregulated in the Gas of mice exposed to CS, while TSA effectively inhibited HDAC1/2 protein levels and attenuated the loss of body weight and skeletal muscle wet weight induced by CS exposure. Markers for ubiquitin degradation, muscle differentiation, cytoskeletal proteins, apoptosis and pyroptosis were all upregulated following CS exposure and effectively restored by TSA.. TSA may inhibit skeletal muscle atrophy and histomorphological alterations induced by CS exposure by downregulating markers of ubiquitin degradation, muscle fiber differentiation, cytoskeletal proteins, apoptosis and pyroptosis via HDAC1/2 inhibition.

Topics: Animals; Apoptosis; Cytoskeletal Proteins; Female; Histone Deacetylase 1; Histone Deacetylase Inhibitors; Hydroxamic Acids; Mice; Mice, Inbred C57BL; Muscle, Skeletal; Muscular Atrophy; Smoking

Quercetin, a flavonol, displays anti-inflammatory and anti-cancer properties. This study aimed to investigate whether a diet containing 0.1% or 1% quercetin (LQ and HQ, respectively) enhances the anti-tumor effects of trichostatin A (TSA) and prevents muscle wasting induced by TSA. The positive control group received quercetin intraperitoneally (IQ). Three weeks after injecting A549 cells, nude mice were given TSA alone or in combination with quercetin administered orally or intraperitoneally for 16 weeks. Tumor volumes as well as body, muscle and epididymal fat weights were determined during or after the experiment. Quercetin given as a diet supplement dose-dependently enhanced the anti-tumor potency of TSA (p < 0.05). The enhancing effect of HQ was similar to that of IQ. HQ also significantly increased the expression of p53, a tumor suppressor, in tumor tissues compared with the TSA alone group. In addition, TSA-induced loss of gastrocnemius muscle weight was inhibited by oral quercetin in a dose dependent manner; the efficiencies of LQ and HQ were similar to or better than IQ. Moreover, both LQ and HQ decreased TSA-induced activation of Forkhead box O1 (FOXO1), a crucial transcription factor that regulates muscle wasting associated genes. Consistently, LQ and HQ suppressed muscle wasting associated proteins atrophy gene-1 and muscle ring-finger protein-1 expression as well as increased the myosin heavy chain level in the gastrocnemius muscles. Besides, quercetin attenuated TSA-increased oxidative damage and proinflammatory cytokines (p < 0.05). These findings demonstrate that a diet containing 0.1% or 1% quercetin enhances the antitumor effect of TSA and prevents TSA-induced muscle wasting.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Drug Therapy, Combination; Forkhead Box Protein O1; Humans; Hydroxamic Acids; Male; Mice; Mice, Nude; Muscle, Skeletal; Muscular Atrophy; Myosin Heavy Chains; Neoplasms; Quercetin

Motor neuron loss and neurogenic atrophy are hallmarks of spinal muscular atrophy (SMA), a leading genetic cause of infant deaths. Previous studies have focused on deciphering disease pathogenesis in motor neurons. However, a systematic evaluation of atrophy pathways in muscles is lacking. Here, we show that these pathways are differentially activated depending on severity of disease in two different SMA model mice. Although proteasomal degradation is induced in skeletal muscle of both models, autophagosomal degradation is present only in Smn(2B/-) mice but not in the more severe Smn(-/-); SMN2 mice. Expression of FoxO transcription factors, which regulate both proteasomal and autophagosomal degradation, is elevated in Smn(2B/-) muscle. Remarkably, administration of trichostatin A reversed all molecular changes associated with atrophy. Cardiac muscle also exhibits differential induction of atrophy between Smn(2B/-) and Smn(-/-); SMN2 mice, albeit in the opposite direction to that of skeletal muscle. Altogether, our work highlights the importance of cautious analysis of different mouse models of SMA as distinct patterns of atrophy induction are at play depending on disease severity. We also revealed that one of the beneficial impacts of trichostatin A on SMA model mice is via attenuation of muscle atrophy through reduction of FoxO expression to normal levels.

Topics: Animals; Cell Cycle Proteins; Disease Models, Animal; Forkhead Box Protein O3; Forkhead Transcription Factors; Gene Expression; Humans; Hydroxamic Acids; Membrane Proteins; Mice, Knockout; Microscopy, Electron, Transmission; Mitochondrial Proteins; Muscle, Skeletal; Muscular Atrophy; Muscular Atrophy, Spinal; Signal Transduction; Survival of Motor Neuron 2 Protein

Skeletal muscle atrophy is commonly associated with immobilization, ageing, and catabolic diseases such as diabetes and cancer cachexia. Epigenetic regulation of gene expression resulting from chromatin remodeling through histone acetylation has been implicated in muscle disuse. The present work was designed to test the hypothesis that treatment with trichostatin A (TSA), a histone deacetylase inhibitor, would partly counteract unloading-induced muscle atrophy. Soleus muscle atrophy (-38%) induced by 14 days of rat hindlimb suspension was reduced to only 25% under TSA treatment. TSA partly prevented the loss of type I and IIa fiber size and reversed the transitions of slow-twitch to fast-twitch fibers in soleus muscle. Unloading or TSA treatment did not affect myostatin gene expression and follistatin protein. Soleus protein carbonyl content remained unchanged, whereas the decrease in glutathione vs. glutathione disulfide ratio and the increase in catalase activity (biomarkers of oxidative stress) observed after unloading were abolished by TSA treatment. The autophagy-lysosome pathway (Bnip3 and microtubule-associated protein 1 light chain 3 proteins, Atg5, Gabarapl1, Ulk1, and cathepsin B and L mRNA) was not activated by unloading or TSA treatment. However, TSA suppressed the rise in muscle-specific RING finger protein 1 (MuRF1) caused by unloading without affecting the forkhead box (Foxo3) transcription factor. Prevention of muscle atrophy by TSA might be due to the regulation of the skeletal muscle atrophy-related MuRF1 gene. Our findings suggest that TSA may provide a novel avenue to treat unloaded-induced muscle atrophy.

Topics: Animals; Disease Models, Animal; Female; Hindlimb Suspension; Histone Deacetylase Inhibitors; Hydroxamic Acids; Muscle Fibers, Fast-Twitch; Muscle Fibers, Slow-Twitch; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Phenotype; Rats, Wistar; RNA, Messenger; Time Factors; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Up-Regulation

Muscle wasting during sepsis is in part regulated by glucocorticoids. In recent studies, treatment of cultured muscle cells in vitro with dexamethasone upregulated expression and activity of p300, a histone acetyl transferase (HAT), and reduced expression and activity of the histone deacetylases-3 (HDAC3) and -6, changes that favor hyperacetylation. Here, we tested the hypothesis that sepsis and glucocorticoids regulate p300 and HDAC3 and -6 in skeletal muscle in vivo. Because sepsis-induced metabolic changes are particularly pronounced in white, fast-twitch skeletal muscle, most experiments were performed in extensor digitorum longus muscles. Sepsis in rats upregulated p300 mRNA and protein levels, stimulated HAT activity, and reduced HDAC6 expression and HDAC activity. The sepsis-induced changes in p300 and HDAC expression were prevented by the glucocorticoid receptor antagonist RU38486. Treatment of rats with dexamethasone increased expression of p300 and HAT activity, reduced expression of HDAC3 and -6, and inhibited HDAC activity. Finally, treatment with the HDAC inhibitor trichostatin A resulted in increased muscle proteolysis and expression of the ubiquitin ligase atrogin-1. Taken together, our results suggest for the first time that sepsis-induced muscle wasting may be regulated by glucocorticoid-dependent hyperacetylation caused by increased p300 and reduced HDAC expression and activity. The recent development of pharmacological HDAC activators may provide a novel avenue to prevent and treat muscle wasting in sepsis and other catabolic conditions.

Topics: Animals; Dexamethasone; Disease Models, Animal; Down-Regulation; E1A-Associated p300 Protein; Gene Expression Regulation, Enzymologic; Glucocorticoids; Histone Deacetylase 6; Histone Deacetylase Inhibitors; Histone Deacetylases; Hormone Antagonists; Hydroxamic Acids; Male; Mifepristone; Muscle Proteins; Muscle, Skeletal; Muscular Atrophy; Rats; Rats, Sprague-Dawley; Receptors, Glucocorticoid; RNA, Messenger; Sepsis; Sirtuin 1; SKP Cullin F-Box Protein Ligases; Time Factors; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Up-Regulation

Muscle wasting, as occurring in cancer cachexia, is primarily characterized by protein hypercatabolism and increased expression of ubiquitin ligases, such as atrogin-1/MAFbx and MuRF-1. Myostatin, a member of the TGFbeta superfamily, negatively regulates skeletal muscle mass and we showed that increased myostatin signaling occurs in experimental cancer cachexia. On the other hand, enhanced expression of follistatin, an antagonist of myostatin, by inhibitors of histone deacetylases, such as valproic acid or trichostatin-A, has been shown to increase myogenesis and myofiber size in mdx mice. For this reason, in the present study we evaluated whether valproic acid or trichostatin-A can restore muscle mass in C26 tumor-bearing mice. Tumor growth induces a marked and progressive loss of body and muscle weight, associated with increased expression of myostatin and ubiquitin ligases. Treatment with valproic acid decreases muscle myostatin levels and enhances both follistatin expression and the inactivating phosphorylation of GSK-3beta, while these parameters are not affected by trichostatin-A. Neither agent, however, counteracts muscle atrophy or ubiquitin ligase hyperexpression. Therefore, modulation of the myostatin/follistatin axis in itself does not appear sufficient to correct muscle atrophy in cancer cachexia.

Topics: Animals; Cachexia; Colonic Neoplasms; Disease Models, Animal; Drug Evaluation, Preclinical; Enzyme Inhibitors; Follistatin; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Histone Deacetylase Inhibitors; Hydroxamic Acids; Mice; Mice, Inbred BALB C; Muscles; Muscular Atrophy; Myostatin; Neoplasm Transplantation; Ubiquitin-Protein Ligases; Valproic Acid