Artemisinin mimics calorie restriction to trigger mitochondrial biogenesis and compromise telomere shortening in mice

Recent studies have demonstrated that resistance exercise leads not only to muscle hypertrophy, but it also improves mitochondrial function. Because calorie restriction (CR) has been suggested as a way to induce mitochondrial biogenesis, we examined the effects of resistance training with or without CR on muscle weight and key mitochondrial parameters in rat skeletal muscle. Four weeks of resistance training (thrice/wk) resulted in increased gastrocnemius muscle weight by 14% in rats fed ad libitum (AL). The degree of muscle-weight increase via resistance training was lower in rats with CR (7.4%). CR showed no effect on phosphorylation of mammalian target of rapamycin (mTOR) signaling proteins rpS6 and ULK1. Our results revealed that CR resulted in elevated levels of peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) protein, a known master regulator of mitochondrial biogenesis. Resistance training alone also resulted in increased PGC-1α levels in skeletal muscle. The magnitude of the increase in PGC-1α was similar in rats in both the CR and AL groups. Moreover, we found that resistance training with CR resulted in elevated levels of proteins involved in mitochondrial fusion (Opa1 and Mfn1), and oxidative phosphorylation, whereas there was no effect of CR on the fission-regulatory proteins Fis1 and Drp1. These results indicate that CR attenuates resistance training-induced muscle hypertrophy, and that it may enhance mitochondrial adaptations in skeletal muscle.

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Artemisinin mimics calorie restriction to initiate antioxidative responses and compromise telomere shortening

10.7287/peerj.preprints.565v1 ◽

2014 ◽

Cited By ~ 2

Author(s):

Da-Ting Wang ◽

Ming Wu ◽

Si-ming Li ◽

Qian Gao ◽

Qing-Ping Zeng

Keyword(s):

Calorie Restriction ◽

Telomere Maintenance ◽

No Donor ◽

Telomere Shortening ◽

Telomere Attrition ◽

Telomere Elongation ◽

Antioxidative Responses ◽

No Signaling ◽

The Stability ◽

Putative Mechanism

Calorie restriction (CR) is known to extend lifespan among organisms with the putative mechanism underlying nitric oxide (NO)-enhanced mitochondrial biogenesis. However, whether NO maintains telomere intact that is implicated in life expectancy remains unknown. We report here the artemisinin derivative artesunate in a low concentration up-regulates mitochondrial SIRT3-SOD2 expression among global activation of antioxidative networks via the NO signaling cascade AMPK→Akt→eNOS→SIRT1→PGC-1α. While the NO donor sodium nitroprusside and the NO precursor L-arginine replicate the antioxidative responses, exogenous low-dose hydrogen peroxide also leads to attenuated oxidative stress. The tumor suppressor BRCA1 and other DNA repair partners are down-regulated after scavenging of reactive oxygen species. Upon treatment, telomere shortening is damped without telomerase up-regulation, highlighting telomere maintenance rather than telomere elongation. In conclusion, artesunate can mimic CR to activate antioxidative responses and alleviate telomere attrition via NO signaling, thereby maintaining the stability and integrity of chromosomes, which are the hallmarks of longevity.

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