The AMPK agonist 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation‐associated cachectic muscle wasting
<p dir="ltr">Activation of AMPK has been associated with pro‐atrophic signaling in muscle. However, AMPK also has anti‐inflammatory effects, suggesting that in cachexia, a syndrome of inflammatory‐driven muscle wasting, AMPK activation could be beneficial. Here we show that the AMPK...
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| مؤلفون آخرون: | , , , , , , , , , , , , , , |
| منشور في: |
2018
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إضافة وسم
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| _version_ | 1864513513531113472 |
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| author | Derek T Hall (18629356) |
| author2 | Takla Griss (832356) Jennifer F Ma (18629359) Brenda Janice Sanchez (18629362) Jason Sadek (18629365) Anne Marie K Tremblay (18629368) Souad Mubaid (18629371) Amr Omer (18629374) Rebecca J Ford (18629377) Nathalie Bedard (232947) Arnim Pause (265677) Simon S Wing (18629380) Sergio Di Marco (387749) Gregory R Steinberg (14471628) Russell G Jones (18629383) Imed‐Eddine Gallouzi (18629386) |
| author2_role | author author author author author author author author author author author author author author author |
| author_facet | Derek T Hall (18629356) Takla Griss (832356) Jennifer F Ma (18629359) Brenda Janice Sanchez (18629362) Jason Sadek (18629365) Anne Marie K Tremblay (18629368) Souad Mubaid (18629371) Amr Omer (18629374) Rebecca J Ford (18629377) Nathalie Bedard (232947) Arnim Pause (265677) Simon S Wing (18629380) Sergio Di Marco (387749) Gregory R Steinberg (14471628) Russell G Jones (18629383) Imed‐Eddine Gallouzi (18629386) |
| author_role | author |
| dc.creator.none.fl_str_mv | Derek T Hall (18629356) Takla Griss (832356) Jennifer F Ma (18629359) Brenda Janice Sanchez (18629362) Jason Sadek (18629365) Anne Marie K Tremblay (18629368) Souad Mubaid (18629371) Amr Omer (18629374) Rebecca J Ford (18629377) Nathalie Bedard (232947) Arnim Pause (265677) Simon S Wing (18629380) Sergio Di Marco (387749) Gregory R Steinberg (14471628) Russell G Jones (18629383) Imed‐Eddine Gallouzi (18629386) |
| dc.date.none.fl_str_mv | 2018-05-29T03:00:00Z |
| dc.identifier.none.fl_str_mv | 10.15252/emmm.201708307 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/The__AMPK__agonist_5_aminoimidazole_4_carboxamide_ribonucleotide_AICAR_but_not_metformin_prevents_inflammation_associated_cachectic_muscle_wasting/25920217 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biomedical and clinical sciences Clinical sciences Psychology Biological psychology AMPK cachexia inflammation iNOS metabolism |
| dc.title.none.fl_str_mv | The AMPK agonist 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation‐associated cachectic muscle wasting |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">Activation of AMPK has been associated with pro‐atrophic signaling in muscle. However, AMPK also has anti‐inflammatory effects, suggesting that in cachexia, a syndrome of inflammatory‐driven muscle wasting, AMPK activation could be beneficial. Here we show that the AMPK agonist AICAR suppresses IFNγ/TNFα‐induced atrophy, while the mitochondrial inhibitor metformin does not. IFNγ/TNFα impair mitochondrial oxidative respiration in myotubes and promote a metabolic shift to aerobic glycolysis, similarly to metformin. In contrast, AICAR partially restored metabolic function. The effects of AICAR were prevented by the AMPK inhibitor Compound C and were reproduced with A‐769662, a specific AMPK activator. AICAR and A‐769662 co‐treatment was found to be synergistic, suggesting that the anti‐cachectic effects of these drugs are mediated through AMPK activation. AICAR spared muscle mass in mouse models of cancer and LPS induced atrophy. Together, our findings suggest a dual function for AMPK during inflammation‐driven atrophy, wherein it can play a protective role when activated exogenously early in disease progression, but may contribute to anabolic suppression and atrophy when activated later through mitochondrial dysfunction and subsequent metabolic stress.</p><h2>Other Information</h2><p dir="ltr">Published in: EMBO Molecular Medicine<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.15252/emmm.201708307" target="_blank">https://dx.doi.org/10.15252/emmm.201708307</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_1e23dedc7f42e6d7954a2f4d27e8097f |
| identifier_str_mv | 10.15252/emmm.201708307 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/25920217 |
| publishDate | 2018 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | The AMPK agonist 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation‐associated cachectic muscle wastingDerek T Hall (18629356)Takla Griss (832356)Jennifer F Ma (18629359)Brenda Janice Sanchez (18629362)Jason Sadek (18629365)Anne Marie K Tremblay (18629368)Souad Mubaid (18629371)Amr Omer (18629374)Rebecca J Ford (18629377)Nathalie Bedard (232947)Arnim Pause (265677)Simon S Wing (18629380)Sergio Di Marco (387749)Gregory R Steinberg (14471628)Russell G Jones (18629383)Imed‐Eddine Gallouzi (18629386)Biomedical and clinical sciencesClinical sciencesPsychologyBiological psychologyAMPKcachexiainflammationiNOSmetabolism<p dir="ltr">Activation of AMPK has been associated with pro‐atrophic signaling in muscle. However, AMPK also has anti‐inflammatory effects, suggesting that in cachexia, a syndrome of inflammatory‐driven muscle wasting, AMPK activation could be beneficial. Here we show that the AMPK agonist AICAR suppresses IFNγ/TNFα‐induced atrophy, while the mitochondrial inhibitor metformin does not. IFNγ/TNFα impair mitochondrial oxidative respiration in myotubes and promote a metabolic shift to aerobic glycolysis, similarly to metformin. In contrast, AICAR partially restored metabolic function. The effects of AICAR were prevented by the AMPK inhibitor Compound C and were reproduced with A‐769662, a specific AMPK activator. AICAR and A‐769662 co‐treatment was found to be synergistic, suggesting that the anti‐cachectic effects of these drugs are mediated through AMPK activation. AICAR spared muscle mass in mouse models of cancer and LPS induced atrophy. Together, our findings suggest a dual function for AMPK during inflammation‐driven atrophy, wherein it can play a protective role when activated exogenously early in disease progression, but may contribute to anabolic suppression and atrophy when activated later through mitochondrial dysfunction and subsequent metabolic stress.</p><h2>Other Information</h2><p dir="ltr">Published in: EMBO Molecular Medicine<br>License: <a href="http://creativecommons.org/licenses/by/4.0/" target="_blank">http://creativecommons.org/licenses/by/4.0/</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.15252/emmm.201708307" target="_blank">https://dx.doi.org/10.15252/emmm.201708307</a></p>2018-05-29T03:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.15252/emmm.201708307https://figshare.com/articles/journal_contribution/The__AMPK__agonist_5_aminoimidazole_4_carboxamide_ribonucleotide_AICAR_but_not_metformin_prevents_inflammation_associated_cachectic_muscle_wasting/25920217CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/259202172018-05-29T03:00:00Z |
| spellingShingle | The AMPK agonist 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation‐associated cachectic muscle wasting Derek T Hall (18629356) Biomedical and clinical sciences Clinical sciences Psychology Biological psychology AMPK cachexia inflammation iNOS metabolism |
| status_str | publishedVersion |
| title | The AMPK agonist 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation‐associated cachectic muscle wasting |
| title_full | The AMPK agonist 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation‐associated cachectic muscle wasting |
| title_fullStr | The AMPK agonist 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation‐associated cachectic muscle wasting |
| title_full_unstemmed | The AMPK agonist 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation‐associated cachectic muscle wasting |
| title_short | The AMPK agonist 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation‐associated cachectic muscle wasting |
| title_sort | The AMPK agonist 5‐aminoimidazole‐4‐carboxamide ribonucleotide (AICAR), but not metformin, prevents inflammation‐associated cachectic muscle wasting |
| topic | Biomedical and clinical sciences Clinical sciences Psychology Biological psychology AMPK cachexia inflammation iNOS metabolism |