Zhou Jin, Chong Shu Yun, Lim Andrea, Singh Brijesh K, Sinha Rohit A, Salmon Adam B, Yen Paul M
Program of Cardiovascular and Metabolic Disorders, Duke-NUS Medical School Singapore, Singapore 169857.
Department of Biomedical Science, Nanyang Technological University, Singapore 637551.
Aging (Albany NY). 2017 Feb 26;9(2):583-599. doi: 10.18632/aging.101181.
Aging causes a general decline in cellular metabolic activity, and function in different tissues and whole body homeostasis. However, the understanding about the metabolomic and autophagy changes in skeletal muscle and heart during aging is still limited. We thus examined markers for macroautophagy, chaperone-mediated autophagy (CMA), mitochondrial quality control, as well as cellular metabolites in skeletal and cardiac muscle from young (5 months old) and aged (27 months old) mice. We found decreased autophagic degradation of p62 and increased ubiquitinated proteins in both tissues from aged mice, suggesting a decline in macroautophagy during aging. In skeletal muscle from aged mice, there also was a decline in LC3B-I conjugation to phosphatidylethanolamine (PE) possibly due to decreased protein levels of ATG3 and ATG12-ATG5. The CMA markers, LAMP-2A and Hsc70, and mitochondrial turnover markers, Drp1, PINK1 and PGC1α also were decreased. Metabolomics analysis showed impaired β-oxidation in heart of aged mice, whereas increased branched-chain amino acids (BCAAs) and ceramide levels were found in skeletal muscle of aged mice that in turn, may contribute to insulin resistance in muscle. Taken together, our studies showed similar declines in macroautophagy but distinct effects on CMA, mitochondrial turnover, and metabolic dysfunction in muscle heart during aging.
衰老会导致细胞代谢活动普遍下降，并影响不同组织的功能和全身稳态。然而，目前对于衰老过程中骨骼肌和心脏的代谢组学及自噬变化的了解仍然有限。因此，我们检测了年轻（5个月大）和老年（27个月大）小鼠骨骼肌和心肌中巨自噬、伴侣介导的自噬（CMA）、线粒体质量控制的标志物以及细胞代谢物。我们发现老年小鼠的这两种组织中p62的自噬降解减少，泛素化蛋白增加，这表明衰老过程中巨自噬功能下降。在老年小鼠的骨骼肌中，LC3B-I与磷脂酰乙醇胺（PE）的结合也有所下降，这可能是由于ATG3和ATG12-ATG5的蛋白水平降低所致。CMA标志物LAMP-2A和Hsc70以及线粒体更新标志物Drp1、PINK1和PGC1α也有所下降。代谢组学分析表明，老年小鼠心脏中的β-氧化受损，而老年小鼠骨骼肌中支链氨基酸（BCAAs）和神经酰胺水平升高，这反过来可能导致肌肉胰岛素抵抗。综上所述，我们的研究表明，衰老过程中巨自噬功能同样下降，但对肌肉和心脏中的CMA、线粒体更新及代谢功能障碍有不同影响。
