Abstract
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 vs. heart during aging.
Highlights
Sarcopenia and decreased cardiac function are common features of the decline in physical performance associated with aging
We saw a significant increase in p62 protein level in muscle and heart from aged mice (Fig. 1A and B), the mRNA levels of p62 were unchanged or decreased in muscle or heart tissue from aged mice, respectively
The reports about the effects of aging on autophagy in skeletal and cardiac muscles are inconsistent as the autophagosome marker, LC3B-II, has been shown to increase [1, 2], decrease [3], or remain unchanged [4, 5], and have led to conflicting views on the role of autophagy in these tissues during aging
Summary
Sarcopenia and decreased cardiac function are common features of the decline in physical performance associated with aging. Aging in the heart is associated with pathological hypertrophy and thickening of the ventricle wall, leading to decreased cardiac output Changes in both metabolism and macroautophagy, a lysosomal-dependent degradation process, have been associated with aging in both these tissues [1,2,3,4,5,6]. Macroautophagy, referred as autophagy in the remainder of this manuscript, is the most studied form www.aging-us.com of autophagic process It involves the formation of double-membrane vesicles termed “autophagosomes”, the sequestration of cytosolic substrate within autophagosomes, and the subsequent fusion of autophagosome and lysosome to form autophagolysosomes, where the engulfed macromolecules such as lipid droplets [7, 8], and glycogen [9] are degraded to provide substrates for cellular metabolism as well as damaged proteins and organelles to maintain cellular homeostasis. There is evidence suggesting a potential role of autophagy in aging, the specific changes in basal levels of autophagy in skeletal and cardiac muscle during the natural aging process and the underlying mechanism(s) have not been well characterized
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