Curcumin induces mitochondrial biogenesis by increasing cyclic AMP levels via phosphodiesterase 4A inhibition in skeletal muscle
Previous research has suggested that curcumin potentially induces mitochondrial biogenesis in skeletal muscle via increasing cyclic AMP (cAMP) levels. However, the regulatory mechanisms for this phenomenon remain unknown. The purpose of the present study was to clarify the mechanism by which curcumi...
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| Veröffentlicht in: | British journal of nutrition 2021-12, Vol.126 (11), p.1642-1650 |
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| creator | Hamidie, Ronald D R Shibaguchi, Tsubasa Yamada, Tatsuya Koma, Rikuhide Ishizawa, Rie Saito, Yoko Hosoi, Tatsunori Masuda, Kazumi |
| description | Previous research has suggested that curcumin potentially induces mitochondrial biogenesis in skeletal muscle via increasing cyclic AMP (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.
The effect of curcumin treatment (i.p., 100 mg/kg-BW/d for 28 d) on mitochondrial biogenesis was determined in rats. The effects of curcumin and exercise (swimming for 2 h/d for 3 d) 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.
Curcumin administration increased cytochrome c oxidase subunit (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 phosphodiesterase 4A (PDE4A), whereas curcumin treatment strongly inhibited PDE4A phosphorylation regardless of exercise. Furthermore, curcumin promoted AMP-activated protein kinase (AMPK) phosphorylation and PPAR gamma coactivator (PGC-1α) deacetylation. Inhibition of PKA abolished the phosphorylation of AMPK.
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 utilises a regulatory mechanism for mitochondrial biogenesis that is distinct from the exercise-induced mechanism in skeletal muscle. |
| doi_str_mv | 10.1017/S0007114521000490 |
| format | Article |
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The effect of curcumin treatment (i.p., 100 mg/kg-BW/d for 28 d) on mitochondrial biogenesis was determined in rats. The effects of curcumin and exercise (swimming for 2 h/d for 3 d) 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.
Curcumin administration increased cytochrome c oxidase subunit (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 phosphodiesterase 4A (PDE4A), whereas curcumin treatment strongly inhibited PDE4A phosphorylation regardless of exercise. Furthermore, curcumin promoted AMP-activated protein kinase (AMPK) phosphorylation and PPAR gamma coactivator (PGC-1α) deacetylation. Inhibition of PKA abolished the phosphorylation of AMPK.
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 utilises a regulatory mechanism for mitochondrial biogenesis that is distinct from the exercise-induced mechanism in skeletal muscle.</description><identifier>ISSN: 0007-1145</identifier><identifier>EISSN: 1475-2662</identifier><identifier>DOI: 10.1017/S0007114521000490</identifier><identifier>PMID: 33551001</identifier><language>eng</language><publisher>Cambridge, UK: Cambridge University Press</publisher><subject>AMP-activated protein kinase ; AMP-Activated Protein Kinases - metabolism ; Animals ; Biosynthesis ; Citrate synthase ; Curcumin ; Curcumin - pharmacology ; Cyclic AMP ; Cyclic AMP - metabolism ; Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism ; Cytochrome-c oxidase ; Cytochromes ; Deacetylation ; Electron transport chain ; Exercise ; Investigations ; Kinases ; Metabolism ; Metabolism and Metabolic Studies ; Mitochondria ; Muscle, Skeletal - metabolism ; Muscles ; Musculoskeletal system ; Organelle Biogenesis ; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism ; Peroxisome proliferator-activated receptors ; Phosphodiesterase ; Phosphorylation ; Physical training ; Polyphenols ; Protein expression ; Protein kinase A ; Proteins ; Rats ; Regulation ; Regulatory mechanisms (biology) ; Respiration ; Signal transduction ; Signaling ; Skeletal muscle ; Swimming ; Transcription Factors - metabolism</subject><ispartof>British journal of nutrition, 2021-12, Vol.126 (11), p.1642-1650</ispartof><rights>The Author(s), 2021. Published by Cambridge University Press on behalf of The Nutrition Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c487t-f17ac70fdabe0607f264e8d1626c04b196d43fd431434e78e3d0fd04cf9519c23</citedby><cites>FETCH-LOGICAL-c487t-f17ac70fdabe0607f264e8d1626c04b196d43fd431434e78e3d0fd04cf9519c23</cites><orcidid>0000-0001-8382-3771</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.cambridge.org/core/product/identifier/S0007114521000490/type/journal_article$$EHTML$$P50$$Gcambridge$$H</linktohtml><link.rule.ids>164,314,780,784,27924,27925,55628</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/33551001$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Hamidie, Ronald D R</creatorcontrib><creatorcontrib>Shibaguchi, Tsubasa</creatorcontrib><creatorcontrib>Yamada, Tatsuya</creatorcontrib><creatorcontrib>Koma, Rikuhide</creatorcontrib><creatorcontrib>Ishizawa, Rie</creatorcontrib><creatorcontrib>Saito, Yoko</creatorcontrib><creatorcontrib>Hosoi, Tatsunori</creatorcontrib><creatorcontrib>Masuda, Kazumi</creatorcontrib><title>Curcumin induces mitochondrial biogenesis by increasing cyclic AMP levels via phosphodiesterase 4A inhibition in skeletal muscle</title><title>British journal of nutrition</title><addtitle>Br J Nutr</addtitle><description>Previous research has suggested that curcumin potentially induces mitochondrial biogenesis in skeletal muscle via increasing cyclic AMP (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.
The effect of curcumin treatment (i.p., 100 mg/kg-BW/d for 28 d) on mitochondrial biogenesis was determined in rats. The effects of curcumin and exercise (swimming for 2 h/d for 3 d) 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.
Curcumin administration increased cytochrome c oxidase subunit (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 phosphodiesterase 4A (PDE4A), whereas curcumin treatment strongly inhibited PDE4A phosphorylation regardless of exercise. Furthermore, curcumin promoted AMP-activated protein kinase (AMPK) phosphorylation and PPAR gamma coactivator (PGC-1α) deacetylation. Inhibition of PKA abolished the phosphorylation of AMPK.
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 utilises a regulatory mechanism for mitochondrial biogenesis that is distinct from the exercise-induced mechanism in skeletal muscle.</description><subject>AMP-activated protein kinase</subject><subject>AMP-Activated Protein Kinases - metabolism</subject><subject>Animals</subject><subject>Biosynthesis</subject><subject>Citrate synthase</subject><subject>Curcumin</subject><subject>Curcumin - pharmacology</subject><subject>Cyclic AMP</subject><subject>Cyclic AMP - metabolism</subject><subject>Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism</subject><subject>Cytochrome-c oxidase</subject><subject>Cytochromes</subject><subject>Deacetylation</subject><subject>Electron transport chain</subject><subject>Exercise</subject><subject>Investigations</subject><subject>Kinases</subject><subject>Metabolism</subject><subject>Metabolism and Metabolic Studies</subject><subject>Mitochondria</subject><subject>Muscle, Skeletal - metabolism</subject><subject>Muscles</subject><subject>Musculoskeletal system</subject><subject>Organelle Biogenesis</subject><subject>Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism</subject><subject>Peroxisome proliferator-activated receptors</subject><subject>Phosphodiesterase</subject><subject>Phosphorylation</subject><subject>Physical training</subject><subject>Polyphenols</subject><subject>Protein expression</subject><subject>Protein kinase A</subject><subject>Proteins</subject><subject>Rats</subject><subject>Regulation</subject><subject>Regulatory mechanisms (biology)</subject><subject>Respiration</subject><subject>Signal transduction</subject><subject>Signaling</subject><subject>Skeletal muscle</subject><subject>Swimming</subject><subject>Transcription Factors - metabolism</subject><issn>0007-1145</issn><issn>1475-2662</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2021</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNp1kU9v1DAQxS1ERZfCB-CCLHHhEupJHDs5rlb8qVQEEnCOHHuy6-LEi51U2ls_OrPqUiRQDyN7NL_3ZqTH2CsQ70CAvvwmhNAAsi6BfrIVT9gKpK6LUqnyKVsdx8Vxfs6e53xDbQOifcbOq6quSQIrdrdZkl1GP3E_ucVi5qOfo93FySVvAu993OKE2WfeH4ixCU3205bbgw3e8vXnrzzgLYbMb73h-13MVM5jnjGZjFyuSbXzvZ99PC7h-ScGnMl6XLIN-IKdDSZkfHl6L9iPD--_bz4V118-Xm3W14WVjZ6LAbSxWgzO9CiU0EOpJDYOVKmskD20yslqoAJZSdQNVo5gIe3Q1tDasrpgb-999yn-Wui8bvTZYghmwrjkrqQ1pK5VS-ibf9CbuKSJruvKulWVgEZrouCesinmnHDo9smPJh06EN0xnu6_eEjz-uS89CO6B8WfPAioTqZm7JN3W_y7-3Hb3_smmpg</recordid><startdate>20211214</startdate><enddate>20211214</enddate><creator>Hamidie, Ronald D R</creator><creator>Shibaguchi, Tsubasa</creator><creator>Yamada, Tatsuya</creator><creator>Koma, Rikuhide</creator><creator>Ishizawa, Rie</creator><creator>Saito, Yoko</creator><creator>Hosoi, Tatsunori</creator><creator>Masuda, Kazumi</creator><general>Cambridge University Press</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>3V.</scope><scope>7QP</scope><scope>7RV</scope><scope>7T5</scope><scope>7X2</scope><scope>7X7</scope><scope>7XB</scope><scope>88E</scope><scope>8C1</scope><scope>8FE</scope><scope>8FH</scope><scope>8FI</scope><scope>8FJ</scope><scope>8FK</scope><scope>8G5</scope><scope>ABUWG</scope><scope>AFKRA</scope><scope>AN0</scope><scope>ATCPS</scope><scope>AZQEC</scope><scope>BENPR</scope><scope>BHPHI</scope><scope>CCPQU</scope><scope>DWQXO</scope><scope>FYUFA</scope><scope>GHDGH</scope><scope>GNUQQ</scope><scope>GUQSH</scope><scope>H94</scope><scope>HCIFZ</scope><scope>K9.</scope><scope>KB0</scope><scope>M0K</scope><scope>M0S</scope><scope>M1P</scope><scope>M2O</scope><scope>MBDVC</scope><scope>NAPCQ</scope><scope>PQEST</scope><scope>PQQKQ</scope><scope>PQUKI</scope><scope>Q9U</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-8382-3771</orcidid></search><sort><creationdate>20211214</creationdate><title>Curcumin induces mitochondrial biogenesis by increasing cyclic AMP levels via phosphodiesterase 4A inhibition in skeletal muscle</title><author>Hamidie, Ronald D R ; Shibaguchi, Tsubasa ; Yamada, Tatsuya ; Koma, Rikuhide ; Ishizawa, Rie ; Saito, Yoko ; Hosoi, Tatsunori ; Masuda, Kazumi</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c487t-f17ac70fdabe0607f264e8d1626c04b196d43fd431434e78e3d0fd04cf9519c23</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2021</creationdate><topic>AMP-activated protein kinase</topic><topic>AMP-Activated Protein Kinases - metabolism</topic><topic>Animals</topic><topic>Biosynthesis</topic><topic>Citrate synthase</topic><topic>Curcumin</topic><topic>Curcumin - pharmacology</topic><topic>Cyclic AMP</topic><topic>Cyclic AMP - metabolism</topic><topic>Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism</topic><topic>Cytochrome-c oxidase</topic><topic>Cytochromes</topic><topic>Deacetylation</topic><topic>Electron transport chain</topic><topic>Exercise</topic><topic>Investigations</topic><topic>Kinases</topic><topic>Metabolism</topic><topic>Metabolism and Metabolic Studies</topic><topic>Mitochondria</topic><topic>Muscle, Skeletal - metabolism</topic><topic>Muscles</topic><topic>Musculoskeletal system</topic><topic>Organelle Biogenesis</topic><topic>Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism</topic><topic>Peroxisome proliferator-activated receptors</topic><topic>Phosphodiesterase</topic><topic>Phosphorylation</topic><topic>Physical training</topic><topic>Polyphenols</topic><topic>Protein expression</topic><topic>Protein kinase A</topic><topic>Proteins</topic><topic>Rats</topic><topic>Regulation</topic><topic>Regulatory mechanisms (biology)</topic><topic>Respiration</topic><topic>Signal transduction</topic><topic>Signaling</topic><topic>Skeletal muscle</topic><topic>Swimming</topic><topic>Transcription Factors - 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Academic</collection><jtitle>British journal of nutrition</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hamidie, Ronald D R</au><au>Shibaguchi, Tsubasa</au><au>Yamada, Tatsuya</au><au>Koma, Rikuhide</au><au>Ishizawa, Rie</au><au>Saito, Yoko</au><au>Hosoi, Tatsunori</au><au>Masuda, Kazumi</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Curcumin induces mitochondrial biogenesis by increasing cyclic AMP levels via phosphodiesterase 4A inhibition in skeletal muscle</atitle><jtitle>British journal of nutrition</jtitle><addtitle>Br J Nutr</addtitle><date>2021-12-14</date><risdate>2021</risdate><volume>126</volume><issue>11</issue><spage>1642</spage><epage>1650</epage><pages>1642-1650</pages><issn>0007-1145</issn><eissn>1475-2662</eissn><abstract>Previous research has suggested that curcumin potentially induces mitochondrial biogenesis in skeletal muscle via increasing cyclic AMP (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.
The effect of curcumin treatment (i.p., 100 mg/kg-BW/d for 28 d) on mitochondrial biogenesis was determined in rats. The effects of curcumin and exercise (swimming for 2 h/d for 3 d) 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.
Curcumin administration increased cytochrome c oxidase subunit (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 phosphodiesterase 4A (PDE4A), whereas curcumin treatment strongly inhibited PDE4A phosphorylation regardless of exercise. Furthermore, curcumin promoted AMP-activated protein kinase (AMPK) phosphorylation and PPAR gamma coactivator (PGC-1α) deacetylation. Inhibition of PKA abolished the phosphorylation of AMPK.
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 utilises a regulatory mechanism for mitochondrial biogenesis that is distinct from the exercise-induced mechanism in skeletal muscle.</abstract><cop>Cambridge, UK</cop><pub>Cambridge University Press</pub><pmid>33551001</pmid><doi>10.1017/S0007114521000490</doi><tpages>9</tpages><orcidid>https://orcid.org/0000-0001-8382-3771</orcidid></addata></record> |
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| subjects | AMP-activated protein kinase AMP-Activated Protein Kinases - metabolism Animals Biosynthesis Citrate synthase Curcumin Curcumin - pharmacology Cyclic AMP Cyclic AMP - metabolism Cyclic Nucleotide Phosphodiesterases, Type 4 - metabolism Cytochrome-c oxidase Cytochromes Deacetylation Electron transport chain Exercise Investigations Kinases Metabolism Metabolism and Metabolic Studies Mitochondria Muscle, Skeletal - metabolism Muscles Musculoskeletal system Organelle Biogenesis Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha - metabolism Peroxisome proliferator-activated receptors Phosphodiesterase Phosphorylation Physical training Polyphenols Protein expression Protein kinase A Proteins Rats Regulation Regulatory mechanisms (biology) Respiration Signal transduction Signaling Skeletal muscle Swimming Transcription Factors - metabolism |
| title | Curcumin induces mitochondrial biogenesis by increasing cyclic AMP levels via phosphodiesterase 4A inhibition in skeletal muscle |
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