AICAR stimulates mitochondrial biogenesis and BCAA catabolic enzyme expression in C2C12 myotubes

Hinkle, Jason S.; Rivera, Caroline N.; Vaughan, Roger A.

doi:10.1016/j.biochi.2021.11.004

Cited by 10 publications

(9 citation statements)

References 37 publications

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“…Interestingly, melatonin treatment rescued the LPS‐stimulated depression‐like behaviour in ApoE4 transgenic mice (Figure 1G–J). Similar results were also observed with UA and AICAR treatment, activators of mitochondrial biogenesis and mitophagy 36,37 …”

Section: Resultsmentioning

confidence: 99%

“…Similar results were also observed with UA and AICAR treatment, activators of mitochondrial biogenesis and mitophagy. 36 , 37 …”

Section: Resultsmentioning

confidence: 99%

“…Similar results were also observed with UA and AICAR treatment, activators of mitochondrial biogenesis and mitophagy. 36,37 Neuroinflammation coincides with depression, and LPS is a wellknown inflammatory agent. [38][39][40] Herein, we determined whether matory signalling through glial cell activation.…”

Section: Lps Aggravated Depressive-like Behaviours and Neuroinflammat...mentioning

confidence: 99%

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ApoE4 dysregulation incites depressive symptoms and mitochondrial impairments in mice

Li,

Ali,

et al. 2024

J Cellular Molecular Medi

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Apolipoprotein E4 (ApoE4) is involved in the stress‐response processes and is hypothesized to be a risk factor for depression by means of mitochondrial dysfunction. However, their exact roles and underlying mechanisms are largely unknown. ApoE4 transgenic mice (B6. Cg‐ApoEtm1UncCdh18Tg(GFAP−APOE i4)1Hol/J) were subjected to stress (lipopolysaccharides, LPS) to elucidate the aetiology of ApoE4‐induced depression. LPS treatment significantly aggravated depression‐like behaviours, concurrent with neuroinflammation and impaired mitochondrial changes, and melatonin/Urolithin A (UA) + 5‐aminoimidazole‐4‐carboxamide 1‐β‐D‐ribofuranoside (AICAR) reversed these effects in ApoE4 mice. Concurrently, ApoE4 mice exhibited mitophagy deficits, which could be further exacerbated by LPS stimulation, as demonstrated by reduced Atg5, Beclin‐1 and Parkin levels, while PINK1 levels were increased. However, these changes were reversed by melatonin treatment. Additionally, proteomic profiling suggested mitochondria‐related signalling and network changes in ApoE4 mice, which may underlie the exaggerated response to LPS. Furthermore, HEK 293T cells transfected with ApoE4 showed mitochondria‐associated protein and mitophagy defects, including PGC‐1α, TFAM, p‐AMPKα, PINK1 and LC3B impairments. Additionally, it aggravates mitochondrial impairment (particularly mitophagy), which can be attenuated by triggering autophagy. Collectively, ApoE4 dysregulation enhanced depressive behaviour upon LPS stimulation.

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Section: Resultsmentioning

confidence: 99%

“…Similar results were also observed with UA and AICAR treatment, activators of mitochondrial biogenesis and mitophagy. 36 , 37 …”

Section: Resultsmentioning

confidence: 99%

Section: Lps Aggravated Depressive-like Behaviours and Neuroinflammat...mentioning

confidence: 99%

See 1 more Smart Citation

ApoE4 dysregulation incites depressive symptoms and mitochondrial impairments in mice

Li,

Ali,

et al. 2024

J Cellular Molecular Medi

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“…In class 1, mitochondria are located as thin linear structures along muscle fibers, whereas in class 2, mitochondria show a more clustered morphology. As a positive control, we used AICAR, an AMPK‐activator known to boost exercise endurance and induce biogenesis of mitochondria (Fan & Evans, 2017 ; Hinkle et al, 2022 ). Although nonsignificant for any of the conditions (chi‐squared test, p ~ .1), we see a trend where, like AICAR, SLs showed an increase in the percentage of animals with clustered mitochondria (Figure 3b ).…”

Section: Resultsmentioning

confidence: 99%

3′sialyllactose and 6′sialyllactose enhance performance in endurance‐type exercise through metabolic adaptation

Spadaro¹,

Hishida

Matsunaga

et al. 2023

Food Science & Nutrition

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Human milk oligosaccharides (HMOs) belong to a group of multifunctional glycans that are abundantly present in human breast milk. While health effects of neutral oligosaccharides have been investigated extensively, a lot remains unknown regarding health effects of acidic oligosaccharides, such as the two sialyllactoses (SLs), 3′sialyllactose (3′SL), and 6′sialyllactose (6′SL). We utilized Caenorhabditis elegans (C. elegans) to investigate the effects of SLs on exercise performance. Using swimming as an endurance‐type exercise, we found that SLs decrease exhaustion, signifying an increase in endurance that is strongest for 6′SL. Through an unbiased metabolomics approach, we identified changes in energy metabolism that correlated with endurance performance. Further investigation suggested that these metabolic changes were related to adaptations of muscle mitochondria that facilitated a shift from beta oxidation to glycogenolysis during exercise. We found that the effect of SLs on endurance performance required AMPK‐ (aak‐1/aak‐2) and adenosine receptor (ador‐1) signaling. We propose a model where SLs alter the metabolic status in the gut, causing a signal from the intestine to the nervous system toward muscle cells, where metabolic adaptation increases exercise performance. Together, our results underline the potential of SLs in exercise‐associated health and contribute to our understanding of the molecular processes involved in nutritionally‐induced health benefits.

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“…In line with these observations, Lian et al showed activation of myotube 5′-AMP-activated protein kinase (AMPK), a master regulator of energetics which activates PGC-1 α [ 20 ], appears to increase BCAA catabolic enzyme expression and/or activity [ 21 ]. Importantly, however, activation of BCAA catabolism via AMPK activators, such as AICAR during cell culture experiments, might be dependent on concentration and glucose availability [ 22 ], and may reduce BCAA catabolism despite an upregulation of BCAA catabolic enzymes, which may accompany metabolic stress as seen with atrophy [ 23 , 24 ]. Collectively, these observations agree with others demonstrating exercise (another activator of PPAR β / δ , AMPK, and PGC-1 α ) increases BCAA metabolism [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

PPARβ/δ Agonism with GW501516 Increases Myotube PGC-1α Content and Reduces BCAA Media Content Independent of Changes in BCAA Catabolic Enzyme Expression

et al. 2023

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Background. Type 2 diabetes is characterized by reduced insulin sensitivity, elevated blood metabolites, and reduced mitochondrial metabolism with reduced expression of genes governing metabolism such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). PGC-1α regulates the expression of branched-chain amino acid (BCAA) metabolism, and thus, increased circulating BCAA in diabetics may be partially explained by reduced PGC-1α expression. PGC-1α functions in-part through interactions with peroxisome proliferator-activated receptor β/δ (PPARβ/δ). The present report examined the effects of the PPARβ/δ agonism on cell metabolism and related gene/protein expression of cultured myotubes, with a primary emphasis on determining the effects of GW on BCAA disposal and catabolic enzyme expression. Methods. C2C12 myotubes were treated with GW501516 (GW) for up to 24 hours. Mitochondrial and glycolytic metabolism were measured via oxygen consumption and extracellular acidification rate, respectively. Metabolic gene and protein expression were assessed via quantitative real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. Media BCAA content was assessed via liquid chromatography–mass spectrometry (LC/MS). Results. GW significantly increased PGC-1α protein expression, mitochondrial content, and mitochondrial function. GW also significantly reduced BCAA content within culture media following 24-hour treatment; however, expression of BCAA catabolic enzymes/transporter was unchanged. Conclusion. These data confirm the ability of GW to increase muscle PGC-1α content and decrease BCAA media content without affecting BCAA catabolic enzymes/transporter. These findings suggest heightened BCAA uptake (and possibly metabolism) may occur without substantial changes in the protein levels of related cell machinery.

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AICAR stimulates mitochondrial biogenesis and BCAA catabolic enzyme expression in C2C12 myotubes

Cited by 10 publications

References 37 publications

ApoE4 dysregulation incites depressive symptoms and mitochondrial impairments in mice

ApoE4 dysregulation incites depressive symptoms and mitochondrial impairments in mice

3′sialyllactose and 6′sialyllactose enhance performance in endurance‐type exercise through metabolic adaptation

PPARβ/δ Agonism with GW501516 Increases Myotube PGC-1α Content and Reduces BCAA Media Content Independent of Changes in BCAA Catabolic Enzyme Expression

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