Rosiglitazone requires hepatocyte PPARγ expression to promote steatosis in male mice with diet-induced obesity

Endocrinology ◽  
2021 ◽  
Author(s):  
Samuel M Lee ◽  
Jose Muratalla ◽  
Alberto Diaz-Ruiz ◽  
Pablo Remon-Ruiz ◽  
Maximillian McCann ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Severe Obesity ◽  
Therapeutic Potential ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Short Term ◽  
Alcoholic Fatty Liver ◽  
Diet Induced Obesity ◽  
Pparγ Expression ◽  
The Impact

Abstract Thiazolidinediones (TZD) are peroxisome proliferator-activated receptor γ (PPARγ agonists that could reduce hepatic steatosis through their effects in adipose tissue, and therefore have been assessed as potential therapies to treat non-alcoholic fatty liver disease (NAFLD) in humans. However, some studies suggest that expression and activation of hepatocyte PPARγ promotes steatosis and that would limit the benefits of TZD as a NAFLD therapy. To further explore this possibility, we examined the impact of short-term rosiglitazone maleate treatment after the development of moderate or severe diet-induced obesity, in both control and adult-onset hepatocyte-specific PPARγ knockout (Pparg △Hep) mice. Independent of the level of obesity and hepatic PPARγ expression, the TZD treatment enhanced insulin sensitivity, associated with an increase in white adipose tissue (WAT) fat accumulation, consistent with clinical observations. However, TZD treatment increased hepatic TG content, only in control mice with severe obesity. Under these conditions, Pparg △Hep reduced diet-induced steatosis and prevented the steatogenic effects of short-term TZD treatment. In these mice, subcutaneous WAT was enlarged and associated with increased levels of adiponectin, while hepatic levels of phosphorylated AMP-activated protein kinase (AMPK) were also increased. In addition, in mice with severe obesity, the expression of hepatic Cd36, Cidea, Cidec, Fabp4, Fasn, and Scd-1 was increased by TZD in a PPARγ-dependent manner. Taken together, these results demonstrate that hepatocyte PPARγ expression offsets the anti-steatogenic actions of TZD in mice with severe obesity. Therefore, in obese and insulin resistant humans, TZD-mediated activation of hepatocyte PPARγ may limit the therapeutic potential of TZD to treat NAFLD.

scholarly journals RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease

Gut ◽  
2020 ◽  
pp. gutjnl-2020-321767
Author(s):  
Marta B Afonso ◽  
Pedro M Rodrigues ◽  
Miguel Mateus-Pinheiro ◽  
André L Simão ◽  
Maria M Gaspar ◽  
...  
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Fatty Liver Disease ◽  
Body Weight Gain ◽  
Control Diet ◽  
Peroxisome Proliferator ◽  
Functional Link ◽  
Alcoholic Fatty Liver ◽  
The Impact ◽  
Alcoholic Fatty Liver Disease

ObjectiveReceptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD.DesignRIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or Ripk3-deficient (Ripk3−/−) mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks.ResultsRIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly, Ripk3 deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in Ripk3−/− mice. Furthermore, Ripk3 deficiency hampered tumourigenesis. Intriguingly, Ripk3−/− mice displayed increased body weight gain, while lipidomics showed that deletion of Ripk3 shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor γ (PPARγ) was increased in Ripk3−/− mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPARγ in controlling fat deposition and fibrosis.ConclusionHepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression.

scholarly journals Non-Viable Lactobacillus johnsonii JNU3402 Protects against Diet-Induced Obesity

Foods ◽  
2020 ◽  
Vol 9 (10) ◽  
pp. 1494
Author(s):  
Garam Yang ◽  
Eunjeong Hong ◽  
Sejong Oh ◽  
Eungseok Kim
Keyword(s):  
Adipose Tissue ◽  
Body Weight Gain ◽  
Normal Diet ◽  
The Body ◽  
Peroxisome Proliferator ◽  
Lactobacillus Johnsonii ◽  
Peroxisome Proliferator Activated Receptor ◽  
Diet Induced Obesity ◽  
Brown Adipose ◽  
And Function

In this study, the role of non-viable Lactobacillus johnsonii JNU3402 (NV-LJ3402) in diet-induced obesity was investigated in mice fed a high-fat diet (HFD). To determine whether NV-LJ3402 exhibits a protective effect against diet-induced obesity, 7-week-old male C57BL/6J mice were fed a normal diet, an HFD, or an HFD with NV-LJ3402 for 14 weeks. NV-LJ3402 administration was associated with a significant reduction in body weight gain and in liver, epididymal, and inguinal white adipose tissue (WAT) and brown adipose tissue weight in HFD-fed mice. Concomitantly, NV-LJ3402 administration to HFD-fed mice also decreased the triglyceride levels in the plasma and metabolic tissues and slightly improved insulin resistance. Furthermore, NV-LJ3402 enhanced gene programming for energy dissipation in the WATs of HFD-fed mice as well as in 3T3-L1 adipocytes with increased peroxisome proliferator-activated receptor-γ (PPARγ) transcriptional activity, suggesting that the PPARγ pathway plays a key role in mediating the anti-obesity effect of NV-LJ3402 in HFD-fed mice. Furthermore, NV-LJ3402 administration in HFD-fed mice enhanced mitochondrial levels and function in WATs and also increased the body temperature upon cold exposure. Together, these results suggest that NV-LJ3402 could be safely used to develop dairy products that ameliorate diet-induced obesity and hyperlipidemia.

scholarly journals Prostanoid EP4 agonist L-902,688 activates PPARγ and attenuates pulmonary arterial hypertension

2018 ◽  
Vol 314 (3) ◽  
pp. L349-L359 ◽  
Author(s):  
Hsin-Hsien Li ◽  
Hsao-Hsun Hsu ◽  
Gwo-Jyh Chang ◽  
I-Chen Chen ◽  
Wan-Jing Ho ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Vascular Remodeling ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Arterial Remodeling ◽  
Peroxisome Proliferator Activated Receptor ◽  
Pulmonary Arterial ◽  
And Migration ◽  
Pparγ Expression

Prostacyclin agonists that bind the prostacyclin receptor (IP) to stimulate cAMP synthesis are effective vasodilators for the treatment of idiopathic pulmonary arterial hypertension (IPAH), but this signaling may occur through nuclear peroxisome proliferator-activated receptor-γ (PPARγ). There is evidence of scant IP and PPARγ expression but stable prostanoid EP4 receptor (EP4) expression in IPAH patients. Both IP and EP4 functionally couple with stimulatory G protein (Gs), which activates signal transduction. We investigated the effect of an EP4-specific agonist on pulmonary arterial remodeling and its regulatory mechanisms in pulmonary arterial smooth muscle cells (PASMCs). Immunoblotting evealed IP, EP4, and PPARγ expression in human pulmonary arterial hypertension (PAH) and monocrotaline (MCT)-induced PAH rat lung tissue. Isolated PASMCs from MCT-induced PAH rats (MCT-PASMCs) were treated with L-902,688, a selective EP4 agonist, to investigate the anti-vascular remodeling effect. Scant expression of IP and PPARγ but stable expression of EP4 was observed in IPAH patient lung tissues and MCT-PASMCs. L-902,688 inhibited IP-insufficient MCT-PASMC proliferation and migration by activating PPARγ in a time- and dose-dependent manner, but these effects were reversed by AH-23848 (an EP4 antagonist) and H-89 [a protein kinase A (PKA) inhibitor], highlighting the crucial role of PPARγ in the activity of this EP4 agonist. L-902,688 attenuated pulmonary arterial remodeling in hypoxic PAH mice and MCT-induced PAH rats; therefore, we conclude that the selective EP4 agonist L-902,688 reverses vascular remodeling by activating PPARγ. This study identified a novel EP4-PKA-PPARγ pathway, and we propose EP4 as a potential therapeutic target for PAH.

scholarly journals Evaluations and Mechanistic Interrogation of Natural Products Isolated From Paeonia suffruticosa for the Treatment of Inflammatory Bowel Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Kun-Chang Wu ◽  
Der-Yen Lee ◽  
Jeh-Ting Hsu ◽  
Chi-Fang Cheng ◽  
Joung-Liang Lan ◽  
...  
Keyword(s):  
Inflammatory Bowel Disease ◽  
Bowel Disease ◽  
Therapeutic Potential ◽  
Ethyl Acetate Fraction ◽  
Root Bark ◽  
Dependent Manner ◽  
Paeonia Suffruticosa ◽  
Inflammatory Bowel ◽  
Anti Inflammatory ◽  
The Impact

Mu Dan Pi (MDP), a traditional Chinese medicine derived from the root bark of Paeonia suffruticosa Andrews, is used to treat autoimmune diseases due to its anti-inflammatory properties. However, the impact of MDP on inflammatory bowel disease (IBD) and its principal active compounds that contribute to the anti-inflammatory properties are uncertain. Thus, this study systemically evaluated the anti-inflammatory effects of fractionated MDP, which has therapeutic potential for IBD. MDP fractions were prepared by multistep fractionation, among which the ethyl acetate-fraction MDP5 exhibited the highest potency, with anti-inflammatory activity screened by the Toll-like receptor (TLR)-2 agonist, Pam3CSK4, in a cell-based model. MDP5 (at 50 μg/ml, p < 0.001) significantly inhibited nuclear factor kappa-B (NF-κB) reporters triggered by Pam3CSK4, without significant cell toxicity. Moreover, MDP5 (at 10 μg/ml) alleviated proinflammatory signaling triggered by Pam3CSK4 in a dose-dependent manner and reduced downstream IL-6 and TNF-α production (p < 0.001) in primary macrophages. MDP5 also mitigated weight loss, clinical inflammation, colonic infiltration of immune cells and cytokine production in a murine colitis model. Index compounds including paeoniflorin derivatives (ranging from 0.1 to 3.4%), gallic acid (1.8%), and 1,2,3,4,6-penta-O-galloyl-β-D-glucose (1.1%) in MDP5 fractions were identified by LC-MS/MS and could be used as anti-inflammatory markers for MDP preparation. Collectively, these data suggest that MDP5 is a promising treatment for IBD patients.

scholarly journals OR14-05 Hepatocyte Peroxisome Proliferator-Activated Receptor Gamma (PPARG) Offsets the Anti-Steatogenic Effects of Thiazolidinediones in Obese Male Mice

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Jose T Muratalla ◽  
Samuel M Lee ◽  
Pablo Remon-Ruiz ◽  
Gregory H Norris ◽  
Jose Cordoba-Chacon
Keyword(s):  
Adipose Tissue ◽  
Insulin Sensitivity ◽  
Liver Weight ◽  
Peroxisome Proliferator ◽  
Dependent Manner ◽  
Peroxisome Proliferator Activated Receptor ◽  
Mild Phenotype ◽  
Insulin Resistant ◽  
Brown Adipose ◽  
Pparg Expression

Abstract Pparg is a nuclear receptor that regulates glucose and lipid metabolism. Thiazolidinediones (TZD) are PPARG agonists that may reduce hepatic steatosis through their effects in adipose tissue. However, some studies suggest that expression and activation of hepatocyte Pparg promotes steatosis. In this study, we have assessed the relevance of hepatocyte Pparg, and its TZD-mediated activation in the development and/or reduction of steatosis, with adult-onset hepatocyte-specific Pparg knockout (PpargΔHep) mice. We reported that a single iv injection of AAV8-TBG-Cre in Pparg-floxed mice, knocked out hepatocyte Pparg expression (PpargΔHep mice), and that prevented diet-induced steatosis. In this study, a group of 5 wk-old Pparg-floxed mice were fed a low fat (LF) or a high fat (HF) diet for 7 weeks before generating control and PpargΔHep mice. Then, half of the HF-fed mice in each group were switched to a HF diet supplemented with the TZD Rosiglitazone maleate, for 5 weeks. HF diet induced mild obesity (36.8 +/- 1.4 g of body weight [BW]), while TZD slightly increased BW (41.3 +/- 1.3 g) and insulin sensitivity. Liver weight was not altered in HF-fed mice with or without TZD, and we did not observe any effect induced by PpargΔHep. Due to the mild phenotype observed in this cohort, we generated a 2nd cohort adjusting for age and length of diet. Briefly, 10 wk-old Pparg-floxed mice were fed a LF or HF diet for 16 weeks before generating control and PpargΔHep mice. Then, half of the HF-fed mice in each group were switched to a HF diet supplemented with Rosiglitazone maleate for 7 weeks. In this group of mice, HF diet induced obesity (50.1 +/- 1.05 g BW), and increased liver weight independent of hepatic Pparg expression. TZD treatment exacerbated obesity (62.4 +/- 1.2g BW) and adiposity, but increased insulin sensitivity as compared to mice fed a HF diet without TZD. Interestingly, PpargΔHep mice fed a HF diet with TZD showed enlarged subcutaneous white and brown adipose tissue weight, and a dramatic reduction in liver weight and steatosis as compared to obese control mice treated with TZD. The expression of hepatic Cd36, Cidea, Cidec, and Fabp4 was increased by TZD in a Pparg-dependent manner in HF-fed mice. Altogether, this data suggest that hepatocyte Pparg expression may offset the antisteatogenic actions of TZD in mice with severe obesity. In obese and insulin resistant individuals, TZD-mediated activation of hepatocyte Pparg may exacerbate steatosis.

scholarly journals Increasing Fat Deposition via Upregulates the Transcription of Peroxisome Proliferator-Activated Receptor Gamma (PPARγ) in Native Crossbred Chicken

2020 ◽  
Author(s):  
Supanon Tunim ◽  
Yupin Phasuk ◽  
Samuel E. Aggrey ◽  
Monchai Duangjinda
Keyword(s):  
Gene Expression ◽  
Adipose Tissue ◽  
Intramuscular Fat ◽  
Abdominal Fat ◽  
Fat Deposition ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Chicken Breeds ◽  
Pparγ Expression ◽  
Pparγ Gene

Abstract Background: Crossbreeding using exotic breeds is usually employed to improve the growth characteristics of indigenous chickens. This mating not only provides growth but affect adversely to fat deposition as well. We studied the growth, abdominal, subcutaneous and intramuscular fat and mRNA expression of peroxisome proliferator-activated receptor (PPAR) α and PPARγ in adipose and muscle tissues of four chicken breeds [Chee breed (CH) (100% Thai native chicken), Kaimook e-san1 (KM1; 50% CH background), Kaimook e-san2 (KM2; 25% CH background), and broiler (BR)]. This study was aim to study role of PPARs on fat deposition in native crossbred chicken.Results: The BR chickens had higher abdominal fat than other breeds (P<0.05) and the KM2 had an abdominal fat percentage higher than KM1 and CH respectively (P<0.05). The intramuscular fat (IMF) of BR was greater than KM1 and CH (P<0.05). In adipose tissue, PPARα transcription expression was different among the chicken breeds. However, there were breed differences in PPARγ gene expression. Study of abdominal fat PPARγ gene expression showed the BR breed, KM1, and KM2 breed significantly greater (P<0.05) than CH. In 8 to 12 weeks of age, the result shows that the PPARγ expression of the CH breed is less than (P<0.05) KM2. The result of PPARs expression in muscle tissue was similar result in adipose tissue.Conclusion: Crossbreeding improved the growth of the Thai native breed, there was also a corresponding increase in carcass fatness. However, there appears to be a relationship between PPARγ expression and fat deposition traits. therefore, PPARγ activity plays a key role in lipid accumulation by up-regulation.

scholarly journals HDL Receptor SR-B1 Deficiency Increased Inflammatory Dyslipidemia and Adipocyte Hypertrophy and Attenuated the Hepatic Steatosis in Murine Diet-Induced Obesity

2020 ◽  
Vol 4 (Supplement_2) ◽  
pp. 1676-1676
Author(s):  
Katherine Rivera ◽  
Veronica Quiñones ◽  
Aline Xavier ◽  
Ludwig Amigo ◽  
Marta Fernández-Galilea ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Fatty Acid ◽  
Hepatic Steatosis ◽  
Fatty Acid Content ◽  
Peroxisome Proliferator ◽  
High Fat ◽  
Alcoholic Fatty Liver ◽  
Knock Out ◽  
Adipocyte Hypertrophy ◽  
Deficient Mice

Abstract Objectives We tested whether the scavenger receptor, class B type 1 (SR-B1), a physiologically relevant HDL receptor, modulates the metabolic and inflammatory phenotype of obese mice, accompanied by changes in adipocyte and hepatocyte lipid deposits. Methods Male SR-B1 knock-out (KO) mice and wild-type (WT) littermates were fed for 12 weeks with a high-fat diet (HFD, n = 12 per group) to induce obesity. Animals were euthanized after overnight food deprivation. Blood was obtained and adipose tissue and liver were removed. Plasma or frozen tissues were used for biochemical analyses or assessed by light microscopy and immunohistochemistry. Comparisons between WT and KO mice fed with HFD were performed and differences were considered statistically significant when P &lt; 0.05. Results Compared to obese WT, obese HFD-fed SR-B1 KO mice showed increased plasma total cholesterol (p &lt; 0.0001) and triglycerides (TG) (p &lt; 0.01) as well as tumor necrosis factor-α (TNF-α) (p &lt; 0.0001) levels. Also, these animals exhibited white fat with larger adipocytes (p &lt; 0.0001) and increased macrophage-based crown-like structure formation (p &lt; 0.01), compared to HFD-fed WT mice, revealing a more inflammatory adipose tissue. These changes in adipose tissue were associated with reduced hepatic steatosis: reduced hepatocyte lipid droplet area (p &lt; 0.0001) and decreased liver TG content (p &lt; 0.0001). In addition, obese SR-B1-deficient mice showed reduced hepatic peroxisome proliferator-activated receptor-γ (PPAR-γ) expression, more efficient hepatic fatty acid β-oxidation and increased very-low-density lipoprotein (VLDL)-TG secretion compared to obese HFD-fed WT mice Furthermore, liver fatty acid (FA) composition in obese SR-B1-deficient mice revealed a reduction in monounsaturated (MUFA) (p &lt; 0.01), but an increase in polyunsaturated (PUFA) (p &lt; 0.05), fatty acid content, compared to obese WT mice. Conclusions Our findings demonstrate that SR-B1 expression modulates high fat feeding-associated inflammatory dyslipidemia, adipocyte hypertrophy, and hepatic steatosis; key processes underlying the pathogenesis of highly prevalent chronic diseases, such as obesity and non-alcoholic fatty liver disease (NAFLD). Funding Sources FONDECYT 1,150,399, FONDECYT 1,180,525.

scholarly journals Brown adipose tissue is involved in the seasonal variation of cold-induced thermogenesis in humans

2016 ◽  
Vol 310 (10) ◽  
pp. R999-R1009 ◽  
Author(s):  
Takeshi Yoneshiro ◽  
Mami Matsushita ◽  
Satoshi Nakae ◽  
Toshimitsu Kameya ◽  
Hiroki Sugie ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Brown Adipose Tissue ◽  
Cold Exposure ◽  
Multivariate Regression Analysis ◽  
Tympanic Temperature ◽  
Whole Body ◽  
Dependent Manner ◽  
Significant Interaction Effect ◽  
Brown Adipose ◽  
The Impact

Brown adipose tissue (BAT) contributes to whole body energy expenditure (EE), especially cold-induced thermogenesis (CIT), in humans. Although it is known that EE and CIT vary seasonally, their relationship with BAT has not been investigated. In the present study, we examined the impact of BAT on seasonal variations of EE/CIT and thermal responses to cold exposure in a randomized crossover design. Forty-five healthy male volunteers participated, and their BAT was assessed by positron emission tomography and computed tomography. CIT, the difference of EE at 27°C and after 2-h cold exposure at 19°C, significantly increased in winter compared with summer, being greater in subjects with metabolically active BAT (High BAT, 185.6 kcal/day vs. 18.3 kcal/day, P < 0.001) than those without (Low BAT, 90.6 kcal/day vs. −46.5 kcal/day, P < 0.05). Multivariate regression analysis revealed a significant interaction effect between season and BAT on CIT ( P < 0.001). The cold-induced drop of tympanic temperature (Tty) and skin temperature (Tskin) in the forehead region and in the supraclavicular region close to BAT deposits were smaller in the High BAT Group than in the Low BAT Group in winter but not in summer. In contrast, the drop of Tskin in the subclavicular and peripheral regions distant from BAT was similar in the two groups in both seasons. In conclusion, CIT increased from summer to winter in a BAT-dependent manner, paralleling cold-induced changes in Tty/Tskin, indicating a role of BAT in seasonal changes in the thermogenic and thermal responses to cold exposure in humans.

scholarly journals Effects of short-term endurance exercise training on acute doxorubicin-induced FoxO transcription in cardiac and skeletal muscle

2014 ◽  
Vol 117 (3) ◽  
pp. 223-230 ◽  
Author(s):  
Andreas N. Kavazis ◽  
Ashley J. Smuder ◽  
Scott K. Powers
Keyword(s):  
Skeletal Muscle ◽  
Exercise Training ◽  
Endurance Exercise ◽  
Skeletal Muscles ◽  
Target Genes ◽  
Ring Finger ◽  
Peroxisome Proliferator ◽  
Short Term ◽  
Peroxisome Proliferator Activated Receptor ◽  
The Impact

Doxorubicin (DOX) is a potent antitumor agent used in cancer treatment. Unfortunately, DOX can induce myopathy in both cardiac and skeletal muscle, which limits its clinical use. Importantly, exercise training has been shown to protect against DOX-mediated cardiac and skeletal muscle myopathy. However, the mechanisms responsible for this exercise-induced muscle protection remain elusive. These experiments tested the hypothesis that short-term exercise training protects against acute DOX-induced muscle toxicity, in part, due to decreased forkhead-box O (FoxO) transcription of atrophy genes. Rats ( n = 6 per group) were assigned to sedentary or endurance exercise-trained groups and paired with either placebo or DOX treatment. Gene expression and protein abundance were measured in both cardiac and skeletal muscles to determine the impact of DOX and exercise on FoxO gene targets. Our data demonstrate that DOX administration amplified FoxO1 and FoxO3 mRNA expression and increased transcription of FoxO target genes [i.e., atrogin-1/muscle atrophy F-box (MaFbx), muscle ring finger-1 (MuRF-1), and BCL2/adenovirus E1B 19 kDa protein-interacting protein 3 (BNIP3)] in heart and soleus muscles. Importantly, exercise training protected against DOX-induced increases of FoxO1 and MuRF-1 in cardiac muscle and also prevented the rise of FoxO3, MuRF-1, and BNIP3 in soleus muscle. Furthermore, our results indicate that exercise increased peroxisome proliferator-activated receptor-gamma coactivator-1 alpha (PGC-1α) in both the heart and soleus muscles. This is important because increased PGC-1α expression is known to suppress FoxO activity resulting in reduced expression of FoxO target genes. Together, these results are consistent with the hypothesis that exercise training protects against DOX-induced myopathy in both heart (FoxO1 and MuRF-1) and skeletal muscles (FoxO3, MuRF-1, and BNIP3).

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