Caffeine promotes autophagy in skeletal muscle cells by increasing the calcium-dependent activation of AMP-activated protein kinase

Mathew, Thresen; Ferris, Robert K.; Downs, R.M.; Kinsey, Stephen T.; Baumgarner, Bradley L.

doi:10.1016/j.bbrc.2014.09.094

Cited by 36 publications

(28 citation statements)

References 25 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We previously demonstrated that caffeine primarily increases AMPK activation in a CaMKKβ-dependent manner in skeletal myotubes (Mathew et al 2014). In the current study, we discovered that the addition of 30 μM STO609 prevented the significant (P < 0.05) reduction in P-S6K1 (Thr389) and P-4EBP1 (Thr37/46) in caffeine vs. vehicle treated skeletal myotubes (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition, activated mTORC1 phosphorylates the eukaryotic translation initiation factor 4E-binding protein 1 (4EBP1), which prevents 4EBP1 from associating with and thus repressing the eukaryotic translation initiation factor 4E (eIF4E) from recruiting the 40S ribosomal subunit to the 5′ end of mRNA (Csibi et al 2010). The AMP-activated protein kinase (AMPK) directly inhibits the activation of mTORC1 in skeletal muscle cells (Mounier et al 2009a, b), and caffeine has been shown to significantly increase AMPK activation in skeletal muscle cells (Egawa et al 2011a, b; Mathew et al 2014). Though caffeine has been shown to significantly reduce mTORC1 activation in numerous mammalian cell lines, it remains unclear if caffeine reduces protein synthesis in skeletal muscle cells in an AMPK-dependent manner.…”

Section: Introductionmentioning

confidence: 99%

“…Our lab recently demonstrated that treating C2C12 skeletal myotubes with 2.5–10 mM caffeine for 6 h promoted a calcium/calmodulin-activated protein kinase kinase β (CaMKKβ) mediated activation of AMPK and a subsequent AMPK-dependent increase in macroautophagy (hereafter referred simply as autophagy) (Mathew et al 2014). However, there is much controversy over the analysis of autophagy in mammalian cells because the initiation of autophagy (autophagosome formation) does not always correlate with increased autolysosome formation and lysosomal degradation, a process referred to as autophagic flux (Klionsky et al 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Caffeine has also been shown to significantly increase the activation of calcium/calmodulin-activated protein kinase II (CaMKII) (Mathew et al 2014). CaMKII is one of the primary upstream kinases of the transcription factor cyclic AMP/calcium response element binding protein (CREB) (Sun et al 1994).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

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

Hughes

Downs

Webb

et al. 2017

J Muscle Res Cell Motil

View full text Add to dashboard Cite

Caffeine is a highly catabolic dietary stimulant. High caffeine concentrations (1–10 mM) have previously been shown to inhibit protein synthesis and increase protein degradation in various mammalian cell lines. The purpose of this study was to examine the effect of short-term caffeine exposure on cell signaling pathways that regulate protein metabolism in mammalian skeletal muscle cells. Fully differentiated C2C12 skeletal myotubes either received vehicle (DMSO) or 5 mM caffeine for 6 h. Our analysis revealed that caffeine promoted a 40% increase in autolysosome formation and a 25% increase in autophagic flux. In contrast, caffeine treatment did not significantly increase the expression of the skeletal muscle specific ubiquitin ligases MAFbx and MuRF1 or 20S proteasome activity. Caffeine treatment significantly reduced mTORC1 signaling, total protein synthesis and myotube diameter in a CaMKKβ/AMPK-dependent manner. Further, caffeine promoted a CaMKII-dependent increase in myostatin mRNA expression that did not significantly contribute to the caffeine-dependent reduction in protein synthesis. Our results indicate that short-term caffeine exposure significantly reduced skeletal myotube diameter by increasing autophagic flux and promoting a CaMKKβ/AMPK-dependent reduction in protein synthesis.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Hughes

Downs

Webb

et al. 2017

J Muscle Res Cell Motil

View full text Add to dashboard Cite

show abstract

“…The total protein concentration of each sample was determined using a Bradford assay. Western blot analysis was conducted using a previously described protocol [26]. Blots were developed using standard ECL detection and images were acquired on a FluorChem E System imager (ProteinSimple, Santa Clara, CA, USA).…”

Section: Methodsmentioning

confidence: 99%

Inhibiting c-Jun N-terminal kinase partially attenuates caffeine-dependent cell death without alleviating the caffeine-induced reduction in mitochondrial respiration in C2C12 skeletal myotubes

Downs

Hughes

Kinsey

et al. 2016

Biochemical and Biophysical Research Communications

Self Cite

View full text Add to dashboard Cite

Caffeine is a widely consumed stimulant that has previously been shown to promote cytotoxic stress and even cell death in numerous mammalian cell lines. Thus far there is little information available regarding the toxicity of caffeine in skeletal muscle cells. Our preliminary data revealed that treating C2C12 myotubes with 5 mM caffeine for 6 h increased nuclear fragmentation and reduced basal and maximal oxygen consumption rate (OCR) in skeletal myotubes. The purpose of this study was to further elucidate the pathways by which caffeine increased cell death and reduced mitochondrial respiration. We specifically examined the role of c-Jun N-terminal kinase (JNK), which has previously been shown to simultaneously increase caspase-dependent cell death and reduce mitochondrial respiration in other mammalian cell lines. We found that caffeine promoted a dose-dependent increase in cell death in multinucleated myotubes but did not in mononucleated myoblasts. The addition of 10 μM Z-DEVD-FMK, a specific inhibitor of executioner caspases, completely inhibited caffeine-dependent cell death. Further, the addition of 400 μM dantrolene, a specific ryanodine receptor (RYR) inhibitor, prevented the caffeine-dependent increase in cell death and the reduction in basal and maximal OCR. We also discovered that caffeine treatment significantly increased the phosphorylation of JNK and that the addition of 30 μM SP600125 (JNKi), a specific JNK inhibitor, partially attenuated caffeine-induced cell death without preventing the caffeine-dependent reduction in basal and maximal OCR. Our results suggest that JNK partially mediates the increase in caspase-dependent cell death but does not contribute to reduced mitochondrial respiration in caffeine-treated skeletal muscle cells. We conclude that caffeine increased cell death and reduced mitochondrial respiration in a calcium-dependent manner by activating the RYR and promoting reticular calcium release.

show abstract

An insight towards anticancer potential of major coffee constituents

et al. 2018

View full text Add to dashboard Cite

Cancer is a complex disease that transforms a normal cell into a malignant cell by disturbing different molecular mechanisms. Lately, plant‐derived bioactive products have gained prominent attention to serve as anti‐cancer agents. These natural anti‐neoplastic agents are believed to act as alternatives for the synthetic drugs or could be used to enhance the prospect of other drugs in reducing their dose, thus limiting their possible toxic effects. They could also counterbalance the other anti‐cancer drug‐induced adverse effects. Among natural plant‐derived products, coffee has been reported for its significant anti‐carcinogenic effects in the scientific literature. This article aims to highlight the anti‐cancer potential of different coffee components viz. caffeic acid, chlorogenic acids, caffeine (1,3,7‐trimethylxanthine), cafestol, ferulic acid, and kahweol together in a single article. Based on our article, it is quite clear that these bioactive components have important therapeutic potentials against cancerous cells. However, the lack of clinical data negates their use in humans. Therefore, more research is recommended to achieve the desired pharmaceutical value. We also implore assessing their safety and possible adverse effects prior to their progress into clinical trials. © 2018 BioFactors, 44(4):315–326, 2018

show abstract

Caffeine promotes autophagy in skeletal muscle cells by increasing the calcium-dependent activation of AMP-activated protein kinase

Cited by 36 publications

References 25 publications

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

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

Inhibiting c-Jun N-terminal kinase partially attenuates caffeine-dependent cell death without alleviating the caffeine-induced reduction in mitochondrial respiration in C2C12 skeletal myotubes

An insight towards anticancer potential of major coffee constituents

Contact Info

Product

Resources

About