FoxO1 induces apoptosis in skeletal myotubes in a DNA-binding-dependent manner

McLoughlin, Thomas J.; Smith, Sierra M.; DeLong, Alissa D.; Wang, Hengbin; Unterman, Terry G.; Esser, Karyn A.

doi:10.1152/ajpcell.00502.2008

Cited by 80 publications

(61 citation statements)

References 36 publications

(42 reference statements)

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“…Whereas activation of MAFbx gene expression requires DNA binding of FoxO1 or FoxO3a, upregulation of MuRF-1 expression was observed independently of DNA binding of forkhead transcription factors. 32,33 Among the healthy controls, aging was associated with a significant decrease in skeletal muscle CSA from 83Ϯ4 cm 2 /82Ϯ2 cm 2 (training and control groups, respectively) to 72Ϯ1 cm 2 /73Ϯ2 cm 2 . Such an age-dependent decline in skeletal muscle CSA was not confirmed among CHF patients, who had reduced CSA, regardless of age, between 69 and 74 cm 2 .…”

Section: Muscle Wasting and Catabolic Activation In Aging And Heart Fmentioning

confidence: 98%

Exercise Training Attenuates MuRF-1 Expression in the Skeletal Muscle of Patients With Chronic Heart Failure Independent of Age

et al. 2012

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Background-Muscle wasting occurs in both chronic heart failure (CHF) and normal aging and contributes to exercise intolerance and increased morbidity/mortality. However, the molecular mechanisms of muscle atrophy in CHF and their interaction with aging are still largely unknown. We therefore measured the activation of the ubiquitin-proteasome system and the lysosomal pathway of intracellular proteolysis in muscle biopsies of CHF patients and healthy controls in two age strata and assessed the age-dependent effects of a 4-week endurance training program on the catabolic-anabolic balance. Methods and Results-Sixty CHF patients (30 patients aged Յ55 years, mean age 46Ϯ5 years; 30 patients aged Ն65 years, mean age 72Ϯ5 years) and 60 healthy controls (30 subjects aged Յ55 years, mean age 50Ϯ5 years; 30 subjects aged Ն65 years, mean age 72Ϯ4 years) were randomized to 4 weeks of supervised endurance training or to a control group. Before and after the intervention, vastus lateralis muscle biopsies were obtained. The expressions of cathepsin-L and the muscle-specific E3 ligases MuRF-1 and MAFbx were measured by real-time polymerase chain reaction and confirmed by Western blot. At baseline, MuRF-1 expression was significantly higher in CHF patients versus healthy controls (mRNA: 624Ϯ59 versus 401Ϯ25 relative units; Pϭ0.007). After 4 weeks of exercise training, MuRF-1 mRNA expression was reduced by Ϫ32.8% (Pϭ0.02) in CHF patients aged Յ55 years and by Ϫ37.0% (PϽ0.05) in CHF patients aged Ն65 years. Conclusions-MuRF-1, a component of the ubiquitin-proteasome system involved in muscle proteolysis, is increased in the skeletal muscle of patients with heart failure. Exercise training results in reduced MuRF-1 levels, suggesting that it blocks ubiquitin-proteasome system activation and does so in both younger and older CHF patients. Clinical Trial Registration-URL: http://www.clinicaltrials.gov. Unique identifier: NCT00176319.

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Section: Muscle Wasting and Catabolic Activation In Aging And Heart Fmentioning

confidence: 98%

Exercise Training Attenuates MuRF-1 Expression in the Skeletal Muscle of Patients With Chronic Heart Failure Independent of Age

et al. 2012

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“…FOXO transcription factors play key roles in cell proliferation, cell cycle, and cellular survival, and are expressed in all cells of the human body (2, 13, 32). In skeletal muscle, FOXO proteins contribute to determine muscle size by regulating the transcription of atrogene products, such as the muscle-specific E3 ligases (5,26,36). Muscle-specific overexpression of FOXO1 or FOXO3a is sufficient to cause skeletal muscle atrophy in vivo (17,36).…”

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confidence: 99%

<b>Changes in FOXO and proinflammatory cytokines in the late stage of immobilized fast and slow muscle atr</b><b>ophy </b>

Okamoto

Machida

2017

Biomed. Res.

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The present study aimed to examine the changes in the expression of Forkhead box protein O (FOXO) and proinflammatory cytokines in both slow-twitch soleus and fast-twitch plantaris muscles following cast immobilization. Male C57BL/6 mice were subjected to cast immobilization for 7 and 21 days. Cast immobilization increased FOXO3a mRNA and total protein expression in both the soleus and plantaris muscles. Although FOXO3a phosphorylation tended to increase in response to cast immobilization in both muscles, a significant increase was evident after 21 days of immobilization only in the soleus muscle. The degree of the response of FOXO3a was very different between the soleus and plantaris muscles; however, the kinetics of FOXO3a in both muscles were similar. Thus, the regulation of muscle atrophy by FOXO might act via a common mechanism in both slow-twitch soleus and fast-twitch plantaris muscles. Gene expression of proinflammatory cytokines tended to increase in response to cast immobilization, and a significant increase was evident after 21 days of immobilization in the soleus muscle. However, in the plantaris muscle, proinflammatory cytokine gene expression remained unchanged throughout the immobilization period; nevertheless, immobilization induced greater reduction in muscle fiber cross-sectional area in the plantaris than in the soleus muscle. Thus, these observations indicate that regulation of muscle atrophy by proinflammatory cytokines might contribute to muscle fiber type-specific mechanisms.Skeletal muscle inactivity resulting from bed rest, microgravity, and immobilization leads to significant muscle atrophy, which not only reduces mobility and quality of life, but also elicits disease and affects overall health (44,45). Muscle atrophy in these conditions is a result of both reduced protein synthesis and increased protein degradation; however, it appears that the latter plays the larger role (21). Protein degradation is mediated primarily through the ubiquitin proteasome pathway (16, 42), and two commonly used markers of this pathway are the muscle-specific E3 ligases, namely muscle atrophy F-box (MAFbx)/atrogin-1, and muscle-specific RING finger 1 (MuRF1) (5, 11). The expressions of both MAFbx/atrogin-1 and MuRF1 are regulated by the Forkhead box protein O (FOXO) family of transcription factors (36,39). FOXO transcription factors play key roles in cell proliferation, cell cycle, and cellular survival, and are expressed in all cells of the human body (2, 13, 32). In skeletal muscle, FOXO proteins contribute to determine muscle size by regulating the transcription of atrogene products, such as the muscle-specific E3 ligases (5,26,36). Muscle-specific overexpression of FOXO1 or FOXO3a is sufficient to cause skeletal muscle atrophy in vivo (17,36). Studies using inactivity-induced atrophy models also report that

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“…Increased mRNA expression of these genes can be used as a marker for the activation of these pathways (15,16). Furthermore, these genes are positively regulated by the transcription factor Forkhead box O1 (FOXO1) (26,30,38). Increased expression of BCL2/adenovirus E1B 19-kDa protein-interacting protein 3 (BNIP3) and microtubule-associated protein 1 light chain-3B (MAP1LC3B) has been used to demonstrate activation of lysosomal protein degradation (3,47).…”

mentioning

confidence: 99%

Distinct responses of protein turnover regulatory pathways in hypoxia- and semistarvation-induced muscle atrophy

Theije¹,

Langen

Lamers³

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

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de Theije CC, Langen RC, Lamers WH, Schols AM, Köhler SE. Distinct responses of protein turnover regulatory pathways in hypoxia-and semistarvation-induced muscle atrophy. Am J Physiol Lung Cell Mol Physiol 305: L82-L91, 2013. First published April 26, 2013 doi:10.1152/ajplung.00354.2012.-The balance of muscle protein synthesis and degradation determines skeletal muscle mass. We hypothesized that hypoxia-induced muscle atrophy and alterations in the regulation of muscle protein turnover include a hypoxia-specific component, in addition to the observed effects of reduction in food intake in response to hypoxia. Mice were subjected to normoxic, hypoxic (8% oxygen), or pair-fed conditions for 2, 4, and 21 days. Cell-autonomous effects of hypoxia on skeletal muscle were also assessed in differentiated C2C12 myotubes. Hypoxia induced an initial rapid loss of body and muscle weight, which remained decreased during chronic hypoxia and could only in part be explained by the hypoxia-induced reduction of food intake (semistarvation). Regulatory steps of protein synthesis (unfolded protein response and mammal target of rapamycin signaling) remained active in response to acute and sustained hypoxia but not to semistarvation. Activation of regulatory signals for protein degradation, including increased expression of Murf1, Atrogin-1, Bnip3, and Map1lc3b mRNAs, was observed in response to acute hypoxia and to a lesser extent following semistarvation. Conversely, the sustained elevation of Atrogin-1, Bnip3, and Map1lc3b mRNAs and the increased activity of their upstream transcriptional regulator Forkhead box O1 were specific to chronic hypoxia because they were not observed in response to reduced food intake. In conclusion, altered regulation of protein turnover during hypoxia-induced muscle atrophy resulted from an interaction of semistarvation and a hypoxia-specific component. The finding that food restriction but not hypoxia-induced semistarvation inhibited regulatory steps in protein synthesis suggests a hypoxiaspecific impairment of the coordination between protein-synthesis signaling and protein-degradation signaling in skeletal muscle. hypoxia; mouse model; protein turnover; regulation; skeletal muscle WEIGHT LOSS AND MUSCLE ATROPHY are common features in advanced chronic obstructive pulmonary disease (COPD). In addition to nutritional imbalance, systemic inflammation, and progressive inactivity, hypoxemia has been implicated as a trigger for muscle atrophy in patients with COPD. Hypoxemia is a symptom during the whole course of the disease with chronic hypoxemia in end-stage COPD and acute hypoxemic episodes during exacerbations (50). Understanding the mechanisms by which hypoxia induces muscle atrophy will benefit the treatment of this disease because loss of muscle mass is a strong predictor of mortality and significantly increases disease burden (8,17,25,35,57). Although exposure to hypobaric hypoxia at high-altitudes results in muscle atrophy in men and animals (5,11,21,23), it is still under debate whether hypoba...

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FoxO1 induces apoptosis in skeletal myotubes in a DNA-binding-dependent manner

Cited by 80 publications

References 36 publications

Exercise Training Attenuates MuRF-1 Expression in the Skeletal Muscle of Patients With Chronic Heart Failure Independent of Age

Exercise Training Attenuates MuRF-1 Expression in the Skeletal Muscle of Patients With Chronic Heart Failure Independent of Age

<b>Changes in FOXO and proinflammatory cytokines in the late stage of immobilized fast and slow muscle atr</b><b>ophy </b>

Distinct responses of protein turnover regulatory pathways in hypoxia- and semistarvation-induced muscle atrophy

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