Curcumin induces mitochondrial biogenesis by increasing cAMP levels via PDE4A inhibition in skeletal muscle

2021 ◽  
pp. 1-34
Author(s):  
Hamidie Ronald D Ray ◽  
Tsubasa Shibaguchi ◽  
Tatsuya Yamada ◽  
Rikuhide Koma ◽  
Rie Ishizawa ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Mitochondrial Biogenesis ◽  
Mitochondrial Respiration ◽  
Citrate Synthase ◽  
Signalling Pathway ◽  
Curcumin Treatment ◽  
Camp Content ◽  
Signalling Molecules ◽  
Camp Levels

Abstract Background: Previous research has suggested that curcumin potentially induces mitochondrial biogenesis in skeletal muscle via increasing cAMP levels. However, the regulatory mechanisms for this phenomenon remain unknown. The purpose of the present study was to clarify the mechanism by which curcumin activates cAMP-related signalling pathways that upregulate mitochondrial biogenesis and respiration in skeletal muscle. Methods: The effect of curcumin treatment (i.p., 100 mg/kg-BW/day for 28 days) on mitochondrial biogenesis was determined in rats. The effects of curcumin and exercise (swimming for 2 h/day for 3 days) on the cAMP signalling pathway were determined in the absence and presence of phosphodiesterase (PDE) or protein kinase A (PKA) inhibitors. Mitochondrial respiration, citrate synthase (CS) activity, cAMP content, and protein expression of cAMP/PKA signalling molecules were analysed. Results: Curcumin administration increased COX-IV protein expression, and CS and complex I activity, consistent with the induction of mitochondrial biogenesis by curcumin. Mitochondrial respiration was not altered by curcumin treatment. Curcumin and PDE inhibition tended to increase cAMP levels with or without exercise. In addition, exercise increased the phosphorylation of PDE4A, whereas curcumin treatment strongly inhibited PDE4A phosphorylation regardless of exercise. Furthermore, curcumin promoted AMPK phosphorylation and PGC-1α deacetylation. Inhibition of PKA abolished the phosphorylation of AMPK. Conclusion: The present results suggest that curcumin increases cAMP levels via inhibition of PDE4A phosphorylation, which induces mitochondrial biogenesis through a cAMP/PKA/AMPK signalling pathway. Our data also suggest the possibility that curcumin utilizes a regulatory mechanism for mitochondrial biogenesis that is distinct from the exercise-induced mechanism in skeletal muscle.

Curcumin treatment enhances the effect of exercise on mitochondrial biogenesis in skeletal muscle by increasing cAMP levels

Metabolism ◽  
2015 ◽  
Vol 64 (10) ◽  
pp. 1334-1347 ◽  
Author(s):  
Ronald D. Ray Hamidie ◽  
Tatsuya Yamada ◽  
Rie Ishizawa ◽  
Yoko Saito ◽  
Kazumi Masuda
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Curcumin Treatment ◽  
Camp Levels

scholarly journals Diverse Action of Selected Statins on Skeletal Muscle Cells—An Attempt to Explain the Protective Effect of Geranylgeraniol (GGOH) in Statin-Associated Myopathy (SAM)

2019 ◽  
Vol 8 (5) ◽  
pp. 694 ◽  
Author(s):  
Anna Jaśkiewicz ◽  
Beata Pająk ◽  
Magdalena Łabieniec-Watała ◽  
Clara De Palma ◽  
Arkadiusz Orzechowski
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Cell Viability ◽  
Mitochondrial Respiration ◽  
Molecular Mechanisms ◽  
Caspase 3 ◽  
C2c12 Cell ◽  
Muscle Cells ◽  
C2c12 Cells ◽  
Calpain Inhibitor

The present study is centered on molecular mechanisms of the cytoprotective effect of geranylgeraniol (GGOH) in skeletal muscle harmed by statin-associated myopathy (SAM). GGOH via autophagy induction was purportedly assumed to prevent skeletal muscle viability impaired by statins, atorvastatin (ATR) or simvastatin (SIM). The C2C12 cell line was used as the ‘in vitro’ model of muscle cells at different stages of muscle formation, and the effect of ATR or SIM on the cell viability, protein expression and mitochondrial respiration were tested. Autophagy seems to be important for the differentiation of muscle cells; however, it did not participate in the observed GGOH cytoprotective effects. We showed that ATR- and SIM-dependent loss in cell viability was reversed by GGOH co-treatment, although GGOH did not reverse the ATR-induced drop in the cytochrome c oxidase protein expression level. It has been unambiguously revealed that the mitochondria of C2C12 cells are not sensitive to SIM, although ATR effectively inhibits mitochondrial respiration. GGOH restored proper mitochondria functioning. Apoptosis might, to some extent, explain the lower viability of statin-treated myotubes as the pan-caspase inhibitor, N-Benzyloxycarbonyl-Val-Ala-Asp(O-Me) fluoromethyl ketone (Z-VAD-FMK), partly reversed ATR- or SIM-induced cytotoxic effects; however, it does not do so in conjunction with caspase-3. It appears that the calpain inhibitor, N-Acetyl-L-leucyl-L-leucyl-L-norleucinal (ALLM), restored the viability that was reduced by ATR and SIM (p < 0.001). GGOH prevents SAM, in part, as a consequence of a caspase-3 independent pathway, probably by calpain system inactivation.

scholarly journals Proteomic changes associated with diabetes in the BB-DP rat

2009 ◽  
Vol 296 (3) ◽  
pp. E422-E432 ◽  
Author(s):  
D. Thor Johnson ◽  
Robert A. Harris ◽  
Stephanie French ◽  
Angel Aponte ◽  
Robert S. Balaban
Keyword(s):  
Mass Spectrometry ◽  
Skeletal Muscle ◽  
Type 1 Diabetes ◽  
Protein Expression ◽  
Gel Electrophoresis ◽  
Citrate Synthase ◽  
Carbon Substrate ◽  
2D Gel Electrophoresis ◽  
2D Gel

These studies were structured with the aim of utilizing emerging technologies in two-dimensional (2D) gel electrophoresis and mass spectrometry to evaluate protein expression changes associated with type 1 diabetes. We reasoned that a broad examination of diabetic tissues at the protein level might open up novel avenues of investigation of the metabolic and signaling pathways that are adversely affected in type 1 diabetes. This study compared the protein expression of the liver, heart, and skeletal muscle of diabetes-prone rats and matched control rats by semiquantitative liquid chromatography-mass spectrometry and differential in-gel 2D gel electrophoresis. Differential expression of 341 proteins in liver, 43 in heart, and 9 (2D gel only) in skeletal muscle was detected. These data were assembled into the relevant metabolic pathways affected primarily in liver. Multiple covalent modifications were also apparent in 2D gel analysis. Several new hypotheses were generated by these data, including mechanisms of net cytosolic protein oxidation, formaldehyde generation by the methionine cycle, and inhibition of carbon substrate oxidation via reduction in citrate synthase and short-chain acyl-CoA dehydrogenase.

scholarly journals Methodological considerations when assessing mitochondrial respiration and biomarkers for mitochondrial content in human skeletal muscle

2021 ◽  
Author(s):  
Jujiao Kuang ◽  
Nicholas J Saner ◽  
Javier Botella ◽  
Matthew J-C Lee ◽  
Cesare Granata ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Respiration ◽  
Coefficient Of Variation ◽  
Human Skeletal Muscle ◽  
Citrate Synthase ◽  
Membrane Integrity ◽  
Mitochondrial Outer Membrane ◽  
Muscle Fibres ◽  
Biological Variability ◽  
Mitochondrial Content

Background: The assessment of mitochondrial respiration and mitochondrial content are two common measurements in the fields of skeletal muscle research and exercise science. However, to verify the validity of the observed changes in both mitochondrial respiration and mitochondrial content following an intervention such as exercise training, it is important to determine the reliability and reproducibility of the experimental design and/or techniques employed. We examined the repeatability of widely used methodologies for assessing mitochondrial respiration and mitochondrial content, respectively; the measurement of maximal mitochondrial oxidative phosphorylation in permeabilized muscle fibres using high-resolution respirometry, and the measurement of citrate synthase activity as a biomarker for mitochondrial content in a microplate with spectrophotometer. Result: For mitochondrial respiration, the coefficient of variation for repeated measurements using muscle sampled from same biopsy decreased from 12.7% to 11% when measured in triplicate with outliers excluded, rather than in duplicate. The coefficient of variation was 9.7% for repeated muscle biopsies sampled across two separated days. For measurements of citrate synthase activity, the coefficient of variation was 3.5% of three technical repeats on the same plate, 10.2% for duplicate analyses using the same muscle lysate when conducted in the same day, and 30.5% when conducted four weeks apart. Conclusion: We have provided evidence for important technical considerations when measuring mitochondrial respiration with human skeletal muscle: 1) the relatively large technical variability can be reduced by increasing technical repeats and excluding outliers; 2) the biological variability and absolute mitochondrial respiration value of the participants should be considered when estimating the required sample size; 3) a new threshold of 15% for the increase in respiration rate after the addition of cytochrome c test for testing mitochondrial outer membrane integrity. When analysing citrate synthase activity, our evidence suggests it is important to consider the following: 1) all samples from the same study should be homogenized and measured at the same time using the same batch of freshly made chemical reagents; 2) biological variability should be considered when detecting small change in mitochondrial content; 3) the relative change should be used to compare the outcomes from different studies.

scholarly journals Nanocurcumin potential to increase mitochondrial biogenesis in skeletal muscle via AMPK-PGC-1alpha

2021 ◽  
Author(s):  
Hamidie Ronald D. Ray ◽  
◽  
Asep Bayu Dani Nandiyanto ◽  
Rita Patriasih ◽  
Abdullah Firmansah ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Protein Expression ◽  
Endurance Exercise ◽  
Mitochondrial Biogenesis ◽  
Curcuma Longa ◽  
Mitochondrial Protein ◽  
Natural Antioxidants ◽  
Adenosine Monophosphate ◽  
Exercise Group ◽  
Mitochondrial Markers

Curcumin, which comes from the rhizome Curcuma longa L, is known as the polyphenol with a high level content of natural antioxidants and has benefits on pharmacological activities and human health. The purpose of current study was to investigate the effect of nanocurcumin itself and the combination with exercise on 5' adenosine monophosphate-activated protein kinase (AMPK), PGC-1α, and mitochondrial protein expression of cytochrome c oxidase subunit IV (COX-IV), in rat gastrocnemius muscle. Animals separated to be non-endurance exercise and endurance exercise group. Curcumin and nanocurcumin with doses 100 mg per kg-body weight per day were given peroral in both groups for 28 days in order to determine the effect of nanocurcumin on mitochondrial markers including AMPK-PGC-1α and COX-IV. Western blotting (WB) method was applied to investigate the protein expression on skeletal muscle. The result showed that nanocurcumin increased mitochondrial marker protein COX-IV on non exercise and exercise groups. Furthermore, our result demonstrated that nanocurcumin treatment combined with exercise increased the phosphorylation of AMPK and PGC-1α. Addition, nanocurcumin treatment alone, without exercise, also increased PGC-1α protein expression. This current result suggests that nanocurcumin could increase mitochondrial biogenesis markers. When it is used together with exercise, it potentially has the additive effect of exercise to increase mitochondrial markers through AMPK-PGC-1α signaling pathway. In conclusion, nanocurcumin treatment combined with exercise potentially increases mitochondrial biogenesis.

Diet-induced vitamin D deficiency reduces skeletal muscle mitochondrial respiration

2021 ◽  
Vol 249 (2) ◽  
pp. 113-124
Author(s):  
Stephen P Ashcroft ◽  
Gareth Fletcher ◽  
Ashleigh M Philp ◽  
Carl Jenkinson ◽  
Shatarupa Das ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Vitamin D ◽  
Protein Content ◽  
Vitamin D Deficiency ◽  
Mitochondrial Function ◽  
Mitochondrial Respiration ◽  
Citrate Synthase ◽  
Current Evidence

Vitamin D deficiency is associated with symptoms of skeletal muscle myopathy including muscle weakness and fatigue. Recently, vitamin D-related metabolites have been linked to the maintenance of mitochondrial function within skeletal muscle. However, current evidence is limited to in vitro models and the effects of diet-induced vitamin D deficiency upon skeletal muscle mitochondrial function in vivo have received little attention. In order to examine the role of vitamin D in the maintenance of mitochondrial function in vivo, we utilised an established model of diet-induced vitamin D deficiency in C57BL/6J mice. Mice were either fed a control diet (2200 IU/kg i.e. vitamin D replete) or a vitamin D-deplete (0 IU/kg) diet for periods of 1, 2 and 3 months. Gastrocnemius muscle mitochondrial function and ADP sensitivity were assessed via high-resolution respirometry and mitochondrial protein content via immunoblotting. As a result of 3 months of diet-induced vitamin D deficiency, respiration supported via complex I + II (CI + IIP) and the electron transport chain (ETC) were 35 and 37% lower when compared to vitamin D-replete mice (P < 0.05). Despite functional alterations, citrate synthase activity, AMPK phosphorylation, mitofilin, OPA1 and ETC subunit protein content remained unchanged in response to dietary intervention (P > 0.05). In conclusion, we report that 3 months of diet-induced vitamin D deficiency reduced skeletal muscle mitochondrial respiration in C57BL/6J mice. Our data, when combined with previous in vitro observations, suggest that vitamin D-mediated regulation of mitochondrial function may underlie the exacerbated muscle fatigue and performance deficits observed during vitamin D deficiency.

Mitochondrial biogenesis during skeletal muscle regeneration

2002 ◽  
Vol 282 (4) ◽  
pp. E802-E809 ◽  
Author(s):  
Stéphanie Duguez ◽  
Léonard Féasson ◽  
Christian Denis ◽  
Damien Freyssenet
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Transcriptional Activation ◽  
Muscle Regeneration ◽  
Citrate Synthase ◽  
Mrna Level ◽  
Skeletal Muscle Regeneration ◽  
Nuclear Antigen ◽  
Peroxisome Proliferator ◽  
Sprague Dawley

Myogenesis requires energy production for the execution of a number of regulatory and biosynthesis events. We hypothesized that mitochondrial biogenesis would be stimulated during skeletal muscle regeneration. Tibialis anterior muscles of male Sprague-Dawley rats were injected with 0.75% bupivacaine and removed at 3, 5, 7, 10, 14, 21, or 35 days after injection ( n = 5–7/group). Two main periods emerged from the histochemical analyses of muscle sections and the expression of proliferating cell nuclear antigen, desmin, and creatine phosphokinase: 1) activation/proliferation of satellite cells ( days 3–14) and 2) differentiation into muscle fibers ( days 5–35). The onset of muscle differentiation was accompanied by a marked stimulation of mitochondrial biogenesis, as indicated by a nearly fivefold increase in citrate synthase activity and state 3 rate of respiration between days 5 and 10. Peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) mRNA level and mitochondrial transcription factor A (mtTFA) protein level peaked on day 10 concurrently with the state 3 rate of respiration. Therefore, transcriptional activation by PGC-1 and mtTFA may be one of the mechanisms regulating mitochondrial biogenesis in regenerating skeletal muscle. Taken together, our results suggest that mitochondrial biogenesis may be an important regulatory event during muscle regeneration.

Functional and biochemical characterization of soleus muscle in Down syndrome mice: insight into the muscle dysfunction seen in the human condition

2012 ◽  
Vol 303 (12) ◽  
pp. R1251-R1260 ◽  
Author(s):  
Patrick M. Cowley ◽  
Stefan Keslacy ◽  
Frank A. Middleton ◽  
Lara R. DeRuisseau ◽  
Bo Fernhall ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Down Syndrome ◽  
Protein Expression ◽  
Muscle Weakness ◽  
Soleus Muscle ◽  
Citrate Synthase ◽  
Human Condition ◽  
Muscle Dysfunction ◽  
Ts65dn Mouse

Persons with Down syndrome (DS) exhibit low muscle strength that significantly impairs their physical functioning. The Ts65Dn mouse model of DS also exhibits muscle weakness in vivo and may be a useful model to examine DS-associated muscle dysfunction. Therefore, the purpose of this experiment was to directly assess skeletal muscle function in the Ts65Dn mouse and to reveal potential mechanisms of DS-associated muscle weakness. Soleus muscles were harvested from anesthetized male Ts65Dn and wild-type (WT) colony controls. In vitro muscle contractile experiments revealed normal force generation of nonfatigued Ts65Dn soleus, but a 12% reduction in force was observed during recovery from fatiguing contractions compared with WT muscle ( P < 0.05). Indicators of oxidative stress and mitochondrial oxidative capacity were assessed to reveal potential mechanisms of DS-associated muscle weakness. Protein expression of copper-zinc superoxide dismutase (SOD1), a triplicated gene in persons with DS and Ts65Dn mice, was increased 25% ( P < 0.05) in Ts65Dn soleus. Nontriplicated antioxidant protein expression was similar between groups. Lipid peroxidation was unaltered in Ts65Dn animals, but protein oxidation was 20% greater compared with controls ( P < 0.05). Cytochrome- c oxidase expression was 22% lower in Ts65Dn muscle ( P < 0.05), while expression of citrate synthase was similar between groups. Microarray analysis revealed alteration of numerous pathways in Ts65Dn muscle, including proteolysis, glucose and fat metabolism, neuromuscular transmission, and ATP biosynthesis. In summary, despite biochemical and gene expression differences in soleus muscle of Ts65Dn animals, the functional properties of skeletal muscle likely contribute a minor part to the in vivo muscle weakness.

scholarly journals Carbon monoxide, skeletal muscle oxidative stress, and mitochondrial biogenesis in humans

2009 ◽  
Vol 297 (1) ◽  
pp. H392-H399 ◽  
Author(s):  
Michael A. Rhodes ◽  
Martha Sue Carraway ◽  
Claude A. Piantadosi ◽  
Crystal M. Reynolds ◽  
Anne D. Cherry ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Carbon Monoxide ◽  
Superoxide Dismutase ◽  
Mitochondrial Biogenesis ◽  
Citrate Synthase ◽  
Vastus Lateralis ◽  
Heme Oxygenase 1 ◽  
Mrna Levels ◽  
Mtdna Copy Number ◽  
Atpase 6

Given that the physiology of heme oxygenase-1 (HO-1) encompasses mitochondrial biogenesis, we tested the hypothesis that the HO-1 product, carbon monoxide (CO), activates mitochondrial biogenesis in skeletal muscle and enhances maximal oxygen uptake (V̇o2max) in humans. In 10 healthy subjects, we biopsied the vastus lateralis and performed V̇o2max tests followed by blinded randomization to air or CO breathing (1 h/day at 100 parts/million for 5 days), a contralateral muscle biopsy on day 5, and repeat V̇o2max testing on day 8. Six independent subjects underwent CO breathing and two muscle biopsies without exercise testing. Molecular studies were performed by real-time RT-PCR, Western blot analysis, and immunochemistry. After V̇o2max testing plus CO breathing, significant increases were found in mRNA levels for nuclear respiratory factor-1, peroxisome proliferator-activated receptor-γ coactivator-1α, mitochondrial transcription factor-A (Tfam), and DNA polymerase γ (Polγ) with no change in mitochondrial DNA (mtDNA) copy number or V̇o2max. Levels of myosin heavy chain I and nuclear-encoded HO-1, superoxide dismutase-2, citrate synthase, mitofusin-1 and -2, and mitochondrial-encoded cytochrome oxidase subunit-I (COX-I) and ATPase-6 proteins increased significantly. None of these responses were reproduced by V̇o2max testing alone, whereas CO alone increased Tfam and Polγ mRNA, and COX-I, ATPase-6, mitofusin-2, HO-1, and superoxide dismutase protein. These findings provide evidence linking the HO/CO response involved in mitochondrial biogenesis in rodents to skeletal muscle in humans through a set of responses involving regulation of the mtDNA transcriptosome and mitochondrial fusion proteins autonomously of changes in exercise capacity.

Induction of an increase in mitochondrial matrix enzymes in muscle of iron-deficient rats

1987 ◽  
Vol 253 (5) ◽  
pp. C639-C644 ◽  
Author(s):  
Y. Ohira ◽  
L. J. Cartier ◽  
M. Chen ◽  
J. O. Holloszy
Keyword(s):  
Skeletal Muscle ◽  
Iron Deficiency ◽  
Mitochondrial Biogenesis ◽  
Citrate Synthase ◽  
Weight Bearing ◽  
Mitochondrial Matrix ◽  
Vigorous Exercise ◽  
Deficient Diet ◽  
Coa Transferase ◽  
Iron Deficient

Young rats maintained on an iron-deficient diet developed severe anemia and had large decreases in the levels of the iron-containing flavoproteins and cytochromes of the mitochondrial respiratory chain in skeletal muscle. In contrast, the levels of a number of mitochondrial matrix marker enzymes, including citrate synthase, isocitrate dehydrogenase, 3-hydroxyacyl-CoA dehydrogenase, 3-ketoacid-CoA transferase, and aspartate aminotransferase, increased in red skeletal muscle but not in white muscle. Phosphocreatine concentration was decreased and inorganic phosphate concentration was increased in soleus muscle frozen in situ. We hypothesize that the increase in mitochondrial matrix enzymes reflects a stimulus to mitochondrial biogenesis in posture-maintaining and weight-bearing red muscle fibers in severely iron-deficient rats. It is our working hypothesis that this stimulus to mitochondrial biogenesis arises from mild activity of the red fibers and is due to the same perturbation in cellular homeostasis that is normally caused by vigorous exercise or hypoxia. In iron deficiency, the stimulus to mitochondrial biogenesis can induce an increase in only those enzymes not prevented from increasing by iron deficiency, resulting in formation of mitochondria of grossly abnormal composition.

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