Atrogin-1 and MuRF1 regulate cardiac MyBP-C levels via different mechanisms

Familial hypertrophic cardiomyopathy (FHC) is frequently caused by cardiac myosin-binding protein C (cMyBP-C) gene mutations, which should result in C-terminal truncated mutants. However, truncated mutants were not detected in myocardial tissue of FHC patients and were rapidly degraded by the ubiquitin-proteasome system (UPS) after gene transfer in cardiac myocytes. Since the diversity and specificity of UPS regulation lie in E3 ubiquitin ligases, we investigated whether the muscle-specific E3 ligases atrogin-1 or muscle ring finger protein-1 (MuRF1) mediate degradation of truncated cMyBP-C

Effects of Antarctic krill oil on lipid and glucose metabolism in C57BL/6J mice fed with high fat diet

Abstract Background Obesity and other metabolic diseases have become epidemic which greatly affect human health. Diets with healthy nutrition are efficient means to prevent this epidemic occurrence. Novel food resources and process technology were needed for these purpose. In this study, Antarctic krill oil (KO) extracted from a dry krill by a procedure of hot pump dehydration in combined with freezing-drying was used to investigate health effect in animals including the growth, lipid and glucose metabolism. Methods C57BL/6J mice were fed with a lard based high fat (HF) diet and substituted with KO for a period of 12 weeks in comparison with low fat normal control (NC) diet. Mice body weight and food consumption were recorded. Serum lipid metabolism - of C57BL/6J mice serum was measured. A glucose tolerance tests (GTTs) and pathology analysis of mice were performed at the end of the experiment. Results The KO fed mice had less body weight gain, less fat accumulation in tissue such as adipose and liver. Dyslipidemia induced by high fat diet was partially improved by KO feeding with significant reduction of serum low density lipoprotein-cholesterol (LDL-C) content. Furthermore, KO feeding also improved glucose metabolism in C57BL/6J mice including a glucose tolerance of about 22% vs. 32% of AUC (area under the curve) for KO vs HF diet and the fast blood glucose level of 8.5 mmol/L, 9.8 mmol/L and 9.3 mmol/L for NC, HF and KO diet groups, respectively. In addition, KO feeding also reduced oxidative damage in liver with a decrease of malondialdehyde (MDA) content and increase of superoxide dismutase (SOD) content. Conclusion This study provided evidence of the beneficial effects of KO on animal health from the processed technology, particularly on lipid and glucose metabolism. This study confirmed that as the Antarctic krill was extracted with a procedure of efficient energy, it might make it possible for Krill oil to be available for food industry

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

SummaryMuscle 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

The muscle-specific ubiquitin ligase atrogin-1/MAFbx mediates statin-induced muscle toxicity

Statins inhibit HMG-CoA reductase, a key enzyme in cholesterol synthesis, and are widely used to treat hypercholesterolemia. These drugs can lead to a number of side effects in muscle, including muscle fiber breakdown; however, the mechanisms of muscle injury by statins are poorly understood. We report that lovastatin induced the expression of atrogin-1, a key gene involved in skeletal muscle atrophy, in humans with statin myopathy, in zebrafish embryos, and in vitro in murine skeletal muscle cells. In cultured mouse myotubes, atrogin-1 induction following lovastatin treatment was accompanied by distinct morphological changes, largely absent in atrogin-1 null cells. In zebrafish embryos, lovastatin promoted muscle fiber damage, an effect that was closely mimicked by knockdown of zebrafish HMG-CoA reductase. Moreover, atrogin-1 knockdown in zebrafish embryos prevented lovastatin-induced muscle injury. Finally, overexpression of PGC-1α, a transcriptional coactivator that induces mitochondrial biogenesis and protects against the development of muscle atrophy, dramatically prevented lovastatin-induced muscle damage and abrogated atrogin-1 induction both in fish and in cultured mouse myotubes. Collectively, our human, animal, and in vitro findings shed light on the molecular mechanism of statin-induced myopathy and suggest that atrogin-1 may be a critical mediator of the muscle damage induced by statins