FoxO3 Coordinately Activates Protein Degradation by the Autophagic/Lysosomal and Proteasomal Pathways in Atrophying Muscle Cells

Department of Cell Biology, Harvard Medical School, Boston, MA 02115, USA.
Cell Metabolism (Impact Factor: 17.57). 01/2008; 6(6):472-83. DOI: 10.1016/j.cmet.2007.11.004
Source: PubMed


Muscle atrophy occurs in many pathological states and results primarily from accelerated protein degradation and activation of the ubiquitin-proteasome pathway. However, the importance of lysosomes in muscle atrophy has received little attention. Activation of FoxO transcription factors is essential for the atrophy induced by denervation or fasting, and activated FoxO3 by itself causes marked atrophy of muscles and myotubes. Here, we report that FoxO3 does so by stimulating overall protein degradation and coordinately activating both lysosomal and proteasomal pathways. Surprisingly, in C2C12 myotubes, most of this increased proteolysis is mediated by lysosomes. Activated FoxO3 stimulates lysosomal proteolysis in muscle (and other cell types) by activating autophagy. FoxO3 also induces the expression of many autophagy-related genes, which are induced similarly in mouse muscles atrophying due to denervation or fasting. These studies indicate that decreased IGF-1-PI3K-Akt signaling activates autophagy not only through mTOR but also more slowly by a transcription-dependent mechanism involving FoxO3.

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    • "In the muscle, FOXO1 and FOXO3 elevate the autophagic flux by increasing the expression of autophagy genes mainly working as part of the core machinery and additionally increase protein degradation via the proteasomal pathway (Sanchez et al. 2014). In particular, FOXO3 increases the capacity of the lysosome to degrade incoming cargo, indicating a role for lysosomal function in muscle atrophy (Zhao et al. 2007). Other FOXOs (FOXO1, FOXO4, and FOXO6) also play roles in proteostasis and autophagy (Lapierre et al. 2015). "
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    ABSTRACT: Age is one of the major risk factors associated with cardiovascular disease (CVD). About one fifth of the world population will be aged 65 or older by 2030 with an exponential increase in CVD prevalence. It is well established that environmental factors (overnutrition, smoking, pollution, sedentary lifestyles) may lead to premature defects in mitochondrial functionality, insulin signalling, endothelial homeostasis and redox balance fostering early senescent features. Over the last few years, molecular investigations unveiled common signalling networks which may link the aging process with deterioration of cardiovascular homeostasis and metabolic disturbances, namely insulin resistance. These different processes seem to be highly interconnected and their interplay may favour adverse vascular and cardiac phenotypes responsible for myocardial infarction, stroke and heart failure. In the present review, we carefully describe novel molecular cues underpinning aging, metabolism and CVD. In particular, we describe a dynamic interplay between emerging pathways such as FOXOs, AMPK, SIRT1, p66(Shc) , JunD and NF-kB. Such an overview will provide the background for attractive molecular targets to prevent age-driven pathology in the vasculature and the heart. This article is protected by copyright. All rights reserved.
    The Journal of Physiology 09/2015; DOI:10.1113/JP270538 · 5.04 Impact Factor
    • "Inhibition of exercise-induced mTORC1 signalling by rapamycin blocked protein synthesis in both human and rodent skeletal muscle (Kubica et al. 2005, Drummond et al. 2009) and prevented muscle hypertrophy induced by overload or the overexpression of constitutively active Akt in mice (Bodine et al. 2001, Pallafacchina et al. 2002). Akt also inactivates Forkhead box Class O (FoxO) transcription factors, which induce muscle atrophy through the expression of numerous atrophy-related genes, including MuRF-1 and atrogin-1 (Zhao et al. 2007). The expression of dominant-negative FoxO in skeletal muscle prevented atrophy in cachectic mice and induced hypertrophy in normal mice (Reed et al. 2012). "
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    Journal of Molecular Endocrinology 09/2015; DOI:10.1530/JME-15-0140 · 3.08 Impact Factor
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    • "When working with T47D cells, knockdown of PSMD2 was introduced for 3 days with doxycycline before bortezomib treatment. For measuring overall rates of protein degradation, pulse-labeling with 3 H-phenylalanine for 24 hr was done before the bortezomib treatment as previously described (Zhao et al., 2007). "
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    ABSTRACT: Proteasomes are central regulators of protein homeostasis in eukaryotes. Proteasome function is vulnerable to environmental insults, cellular protein imbalance and targeted pharmaceuticals. Yet, mechanisms that cells deploy to counteract inhibition of this central regulator are little understood. To find such mechanisms, we reduced flux through the proteasome to the point of toxicity with specific inhibitors and performed genome-wide screens for mutations that allowed cells to survive. Counter to expectation, reducing expression of individual subunits of the proteasome's 19S regulatory complex increased survival. Strong 19S reduction was cytotoxic but modest reduction protected cells from inhibitors. Protection was accompanied by an increased ratio of 20S to 26S proteasomes, preservation of protein degradation capacity and reduced proteotoxic stress. While compromise of 19S function can have a fitness cost under basal conditions, it provided a powerful survival advantage when proteasome function was impaired. This means of rebalancing proteostasis is conserved from yeast to humans.
    eLife Sciences 09/2015; 4. DOI:10.7554/eLife.08467 · 9.32 Impact Factor
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