bims-amsmem 2023-06-18 papers

Issue of 2023–06–18
five papers selected by
Dipsikha Biswas, Københavns Universitet

J Photochem Photobiol B. 2023 Jun 05. pii: S1011-1344(23)00089-1. [Epub ahead of print]245 112735

The AMPK-dependent inhibition of autophagy plays a crucial role in protecting photoreceptor from photooxidative injury.

Yu-Lin Li, Tian-Zi Zhang, Li-Kun Han, Chang He, Yi-Ran Pan, Bin Fan, Guang-Yu Li.

Excessive light exposure can potentially cause irreversible damage to the various photoreceptor cells, and this aspect has been considered as an important factor leading to the progression of the different retinal diseases. AMP-activated protein kinase (AMPK) and the mammalian target of rapamycin (mTOR) are crucial intracellular signaling hubs involved in the regulation of cellular metabolism, energy homeostasis, cellular growth and autophagy. A number of previous studies have indicated that either AMPK activation or mTOR inhibition can promote autophagy in most cases. In the current study, we have established an in vitro as well as in vivo photooxidation-damaged photoreceptor model and investigated the possible influence of visible light exposure in the AMPK/mTOR/autophagy signaling pathway. We have also explored the potential regulatory effects of AMPK/mTOR on light-induced autophagy and protection achieved by suppressing autophagy in photooxidation-damaged photoreceptors. We observed that light exposure led to a significant activation of mTOR and autophagy in the photoreceptor cells. However, intriguingly, AMPK activation or mTOR inhibition significantly inhibited rather than promoting autophagy, which was termed as AMPK-dependent inhibition of autophagy. In addition, either indirectly suppressing autophagy by AMPK activation/ mTOR inhibition or directly blocking autophagy with an inhibitor exerted a significant protective effect on the photoreceptor cells against the photooxidative damage. Neuroprotective effects caused by the AMPK-dependent inhibition of autophagy were also verified with a retinal light injured mouse model in vivo. Overall, our findings demonstrated that AMPK / mTOR pathway could inhibit autophagy through AMPK-dependent inhibition of autophagy to significantly protect the photoreceptors from photooxidative injury, which may aid to further develop novel targeted retinal neuroprotective drugs.

Keywords: AMPK; Autophagy; Photooxidation; Photoreceptor; Retinal light injury; Retinal neuroprotection

DOI: https://doi.org/10.1016/j.jphotobiol.2023.112735

Int J Mol Sci. 2023 May 25. pii: 9263. [Epub ahead of print]24(11):

Exercise Training Attenuates Acute β-Adrenergic Receptor Activation-Induced Cardiac Inflammation via the Activation of AMP-Activated Protein Kinase.

Mi Zhang, Akehu Alemasi, Mingming Zhao, Wenli Xu, Youyi Zhang, Wei Gao, Haiyi Yu, Han Xiao.

Exercise has proven cardiac benefits, but the underlying mechanisms of exercise that protect the heart from acute sympathetic stress injuries remain unknown. In this study, adult C57BL/6J mice and their AMP-activated protein kinase α2 knockout (AMPKα2-/-) littermates were either subjected to 6 weeks of exercise training or housed under sedentary conditions and then treated with or without a single subcutaneous injection of the β-adrenergic receptor (β-AR) agonist isoprenaline (ISO). We investigated the differences in the protective effects of exercise training on ISO-induced cardiac inflammation in wild-type (WT) and AMPKα2-/- mice using histology, enzyme-linked immunosorbent assay (ELISA) and Western blotting analyses. The results indicated that exercise training alleviated ISO-induced cardiac macrophage infiltration, chemokines and the expression of proinflammatory cytokines in wild-type mice. A mechanism study showed that exercise training attenuated the ISO-induced production of reactive oxygen species (ROS) and the activation of NLR Family, pyrin domain-containing 3 (NLRP3) inflammasomes. In cardiomyocytes, the ISO-induced effects on these processes were inhibited by AMP-activated protein kinase (AMPK) activator (metformin) pretreatment and reversed by the AMPK inhibitor (compound C). AMPKα2-/- mice showed more extensive cardiac inflammation following ISO exposure than their wild-type littermates. These results indicated that exercise training could attenuate ISO-induced cardiac inflammation by inhibiting the ROS-NLRP3 inflammasome pathway in an AMPK-dependent manner. Our findings suggested the identification of a novel mechanism for the cardioprotective effects of exercise.

Keywords: AMP-activated protein kinase; NLR family, pyrin domain-containing 3; acute sympathetic stress; exercise training

DOI: https://doi.org/10.3390/ijms24119263

J Cardiovasc Aging. 2023 ;pii: 25. [Epub ahead of print]3(3):

A worm's life: AMPK links muscle mitochondrial dynamics to physical fitness and healthy aging in Caenorhabditis elegans.

Vihang A Narkar.

Keywords: AMPK; Exercise; mitochondrial dynamics

DOI: https://doi.org/10.20517/jca.2023.14

Dev Cell. 2023 Jun 08. pii: S1534-5807(23)00248-4. [Epub ahead of print]

Genetic perturbation of AMP biosynthesis extends lifespan and restores metabolic health in a naturally short-lived vertebrate.

Gwendoline Astre, Tehila Atlan, Uri Goshtchevsky, Adi Oron-Gottesman, Margarita Smirnov, Kobi Shapira, Ariel Velan, Joris Deelen, Tomer Levy, Erez Y Levanon, Itamar Harel.

During aging, the loss of metabolic homeostasis drives a myriad of pathologies. A central regulator of cellular energy, the AMP-activated protein kinase (AMPK), orchestrates organismal metabolism. However, direct genetic manipulations of the AMPK complex in mice have, so far, produced detrimental phenotypes. Here, as an alternative approach, we alter energy homeostasis by manipulating the upstream nucleotide pool. Using the turquoise killifish, we mutate APRT, a key enzyme in AMP biosynthesis, and extend the lifespan of heterozygous males. Next, we apply an integrated omics approach to show that metabolic functions are rejuvenated in old mutants, which also display a fasting-like metabolic profile and resistance to high-fat diet. At the cellular level, heterozygous cells exhibit enhanced nutrient sensitivity, reduced ATP levels, and AMPK activation. Finally, lifelong intermittent fasting abolishes the longevity benefits. Our findings suggest that perturbing AMP biosynthesis may modulate vertebrate lifespan and propose APRT as a promising target for promoting metabolic health.

Keywords: AMP biosynthesis; AMPK; APRT; CRISPR; aging; killifish; longevity; metabolism; nutrient sensing; sex differences

DOI: https://doi.org/10.1016/j.devcel.2023.05.015

Phytother Res. 2023 Jun 14.

DMC (2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone) enhances exercise tolerance via the AMPK-SIRT1-PGC-1α pathway in mice fed a high-fat diet.

Xiaotong Su, Linglin Lai, Xu Li, Wenna Li, Zhentao Mo, Yiqi Li, Lu Xiao, Wenjun Wang, Feng Wang.

Obesity is caused by an imbalance between energy intake and energy expenditure. This study aimed to determine the effects and mechanisms of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) on exercise tolerance in high-fat diet (HFD)-fed mice. Male C57BL/6J mice were randomly divided into two categories (7 groups [n = 8]): sedentary (control [CON], HFD, 200 mg/kg DMC, and 500 mg/kg DMC) and swimming (HFD, 200 mg/kg DMC, and 500 mg/kg DMC). Except the CON group, all other groups were fed HFD with or without DMC intervention for 33 days. The swimming groups were subjected to exhaustive swimming (three sessions/week). Changes in swimming time, glucolipid metabolism, body composition, biochemical indicators, histopathology, inflammation, metabolic mediators, and protein expression were assessed. DMC combined with regular exercise improved endurance performance, body composition, glucose and insulin tolerance, lipid profile, and the inflammatory state in a dose-dependent manner. Further, DMC alone or combined with exercise could restore normal tissue morphology, reduce fatigue-associated markers, and boost whole-body metabolism and the protein expression of phospho-AMP-activated protein kinase alpha/total-AMP-activated protein kinase alpha (AMPK), sirtuin-1 (SIRT1), peroxisome-proliferator-activated receptor gamma coactivator 1alpha (PGC-1α), and peroxisome proliferator-activated receptor alpha in the muscle and adipose tissues of HFD-fed mice. DMC exhibits antifatigue effects by regulating glucolipid catabolism, inflammation, and energy homeostasis. Furthermore, DMC exerts a synergistic exercise-related metabolic effect via the AMPK-SIRT1-PGC-1α signaling pathway, suggesting that DMC is a potential natural sports supplement with mimicked or augmented exercise effects for obesity prevention.

Keywords: 2′,4′-dihydroxy-6′-methoxy-3′,5′-dimethylchalcone; AMPK-SIRT1-PGC-1α; exercise tolerance; glycogen storage; lipid metabolism; obesity

DOI: https://doi.org/10.1002/ptr.7914