Acute high-caffeine exposure increases autophagic flux and reduces protein synthesis in C2C12 skeletal myotubes

Hughes, Michelle A.; Downs, R.M.; Webb, Ginny; Crocker, Chelsea L.; Kinsey, Stephen T.; Baumgarner, Bradley L.

doi:10.1007/s10974-017-9473-9

Cited by 15 publications

(7 citation statements)

References 25 publications

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“…To the best of our knowledge, the present study provides the first evidence that chronic caffeine treatment protects against mutant α-Syn-mediated neurotoxicity by re-establishing macroautophagy signals. This finding is in line with the view that caffeine induces a starvation response with induction of macroautophagy in yeasts (Winter et al, 2008 ; Saiki et al, 2011 ) and induce autophagy in various mammalian cell lines (Mathew et al, 2014 ; Hughes et al, 2017 ). In agreement with this view, caffeine reduces intra-hepatic lipid content and stimulates β-oxidation in hepatic cells with concomitant increase of autophagy and lipid uptake in lysosomes by down-regulation of mammalian target of rapamycin signaling (Sinha et al, 2014 ).…”

Section: Discussionsupporting

confidence: 86%

Chronic Caffeine Treatment Protects Against α-Synucleinopathy by Reestablishing Autophagy Activity in the Mouse Striatum

et al. 2018

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Despite converging epidemiological evidence for the inverse relationship of regular caffeine consumption and risk of developing Parkinson's disease (PD) with animal studies demonstrating protective effect of caffeine in various neurotoxin models of PD, whether caffeine can protect against mutant α-synuclein (α-Syn) A53T-induced neurotoxicity in intact animals has not been examined. Here, we determined the effect of chronic caffeine treatment using the α-Syn fibril model of PD by intra-striatal injection of preformed A53T α-Syn fibrils. We demonstrated that chronic caffeine treatment blunted a cascade of pathological events leading to α-synucleinopathy, including pSer129α-Syn-rich aggregates, apoptotic neuronal cell death, microglia, and astroglia reactivation. Importantly, chronic caffeine treatment did not affect autophagy processes in the normal striatum, but selectively reversed α-Syn-induced defects in macroautophagy (by enhancing microtubule-associated protein 1 light chain 3, and reducing the receptor protein sequestosome 1, SQSTM1/p62) and chaperone-mediated autophagy (CMA, by enhancing LAMP2A). These findings support that caffeine—a strongly protective environment factor as suggested by epidemiological evidence—may represent a novel pharmacological therapy for PD by targeting autophagy pathway.

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Section: Discussionsupporting

confidence: 86%

Chronic Caffeine Treatment Protects Against α-Synucleinopathy by Reestablishing Autophagy Activity in the Mouse Striatum

et al. 2018

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“…Furthermore, we discovered that 0.5 mM caffeine promoted a twofold increase in autophagosome accumulation in 0.5 mM OA‐treated cells (Figure ). Although we have previously demonstrated that caffeine increases autophagy in skeletal myotubes (Hughes et al, ; Mathew et al, ), to the best of our knowledge this is the first investigation to demonstrate that a physiologically relevant dose of caffeine can significantly increase autophagy in mammalian skeletal myotubes.…”

Section: Discussionmentioning

confidence: 61%

“…The popular dietary stimulant caffeine has been shown to increase lipid utilization, mitochondrial biogenesis, and autophagy in skeletal muscle cells treated with very high doses of caffeine (Abbott, Edelman, & Turcotte, ; Ding et al, ; Hughes et al, ; Mathew et al, ). It remains unclear whether lower, more physiologically relevant doses of caffeine can similarly impact lipid metabolism and autophagy in mammalian skeletal muscle cells.…”

Section: Discussionmentioning

confidence: 99%

“…Although caffeine was recently demonstrated to increase cellular lipid utilization in a lipophagy‐dependent manner in murine hepatocytes (Sinha et al, ), it remains unclear whether caffeine can promote lipophagy in skeletal muscle cells. Our laboratory previously demonstrated that higher caffeine doses (2.5–10 mM) significantly increased autophagy in C2C12 murine skeletal myotubes (Hughes et al, ; Mathew, Ferris, Downs, Kinsey, & Baumgarner, ). However, it remains unclear whether lower, more physiologically relevant doses of caffeine can significantly increase autophagy, and possibly lipophagy, in skeletal muscle cells.…”

Section: Introductionmentioning

confidence: 91%

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Low‐dose caffeine administration increases fatty acid utilization and mitochondrial turnover in C2C12 skeletal myotubes

et al. 2020

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Caffeine has been shown to directly increase fatty acid oxidation, in part, by promoting mitochondrial biogenesis. Mitochondrial biogenesis is often coupled with mitophagy, the autophagy-lysosomal degradation of mitochondria. Increased mitochondrial biogenesis and mitophagy promote mitochondrial turnover, which can enhance aerobic metabolism. In addition, recent studies have revealed that cellular lipid droplets can be directly utilized in an autophagy-dependent manner, a process known as lipophagy. Although caffeine has been shown to promote autophagy and mitochondrial biogenesis in skeletal muscles, it remains unclear whether caffeine can increase lipophagy and mitochondrial turnover in skeletal muscle as well. The purpose of this study was to determine the possible contribution of lipophagy to caffeine-dependent lipid utilization. Furthermore, we sought to determine whether caffeine could increase mitochondrial turnover, which may also contribute to elevated fatty acid oxidation. Treating fully differentiated C2C12 skeletal myotubes with 0.5 mM oleic acid (OA) for 24 hr promoted an approximate 2.5fold increase in cellular lipid storage. Treating skeletal myotubes with 0.5 mM OA plus 0.5 mM caffeine for an additional 24 hr effectively returned cellular lipid stores to control levels, and this was associated with an increase in markers of autophagosomes and autophagic flux, as well as elevated autophagosome density in TEM images. The addition of autophagy inhibitors 3-methyladenine (10 mM) or bafilomycin A1 (10 μM) reduced caffeine-dependent lipid utilization by approximately 30%. However, fluorescence and transmission electron microscopy analysis revealed no direct evidence of lipophagy in skeletal myotubes, and there was also no lipophagy-dependent increase in fatty acid oxidation. Finally, caffeine treatment promoted an 80% increase in mitochondrial turnover, which coincided with a 35% increase in mitochondrial fragmentation. Our results suggest that caffeine administration causes an autophagy-dependent decrease in lipid content by increasing mitochondrial turnover in mammalian skeletal myotubes. K E Y W O R D Scaffeine, lipid utilization, mitochondrial turnover, mitophagy, skeletal muscle

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“…Accordingly, caffeine-enhanced autophagic flux in hepatic stellate cells was stimulated by endoplasmic reticulum (ER) stress via the IRE1-α signaling pathway, and autophagy trigged by caffeine instigated cell apoptosis (Li et al, 2017). Acute high-caffeine exposure also significantly reduced skeletal myotube diameter by increasing autophagic flux in differentiated C2C12 mouse skeletal myoblasts cells (Bloemberg and Quadrilatero, 2016;Hughes et al, 2017). Notably, caffeine increased autophagy by promoting the calcium-dependent activation of AMPactivated protein kinase (AMPK) in mammalian skeletal muscle cells (Mathew et al, 2014), and prevent skin from oxidative stress-induced senescence through the activation of autophagy.…”

Section: Caffeine May Modulate Pd Pathology By Regulating Autophagy Amentioning

confidence: 99%

Caffeine and Parkinson’s Disease: Multiple Benefits and Emerging Mechanisms

2020

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder, characterized by dopaminergic neurodegeneration, motor impairment and non-motor symptoms. Epidemiological and experimental investigations into potential risk factors have firmly established that dietary factor caffeine, the most-widely consumed psychoactive substance, may exerts not only neuroprotective but a motor and non-motor (cognitive) benefits in PD. These multi-benefits of caffeine in PD are supported by convergence of epidemiological and animal evidence. At least six large prospective epidemiological studies have firmly established a relationship between increased caffeine consumption and decreased risk of developing PD. In addition, animal studies have also demonstrated that caffeine confers neuroprotection against dopaminergic neurodegeneration using PD models of mitochondrial toxins (MPTP, 6-OHDA, and rotenone) and expression of α-synuclein (α-Syn). While caffeine has complex pharmacological profiles, studies with genetic knockout mice have clearly revealed that caffeine’s action is largely mediated by the brain adenosine A2A receptor (A2AR) and confer neuroprotection by modulating neuroinflammation and excitotoxicity and mitochondrial function. Interestingly, recent studies have highlighted emerging new mechanisms including caffeine modulation of α-Syn degradation with enhanced autophagy and caffeine modulation of gut microbiota and gut-brain axis in PD models. Importantly, since the first clinical trial in 2003, United States FDA has finally approved clinical use of the A2AR antagonist istradefylline for the treatment of PD with OFF-time in Sept. 2019. To realize therapeutic potential of caffeine in PD, genetic study of caffeine and risk genes in human population may identify useful pharmacogenetic markers for predicting individual responses to caffeine in PD clinical trials and thus offer a unique opportunity for “personalized medicine” in PD.

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Acute high-caffeine exposure increases autophagic flux and reduces protein synthesis in C2C12 skeletal myotubes

Cited by 15 publications

References 25 publications

Chronic Caffeine Treatment Protects Against α-Synucleinopathy by Reestablishing Autophagy Activity in the Mouse Striatum

Chronic Caffeine Treatment Protects Against α-Synucleinopathy by Reestablishing Autophagy Activity in the Mouse Striatum

Low‐dose caffeine administration increases fatty acid utilization and mitochondrial turnover in C2C12 skeletal myotubes

Caffeine and Parkinson’s Disease: Multiple Benefits and Emerging Mechanisms

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