Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control
Abstract Background Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously...
| Main Authors: | , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2022-06-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jcsm.12982 |
| _version_ | 1797203475213320192 |
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| author | Wagner S. Dantas Elizabeth R.M. Zunica Elizabeth C. Heintz Bolormaa Vandanmagsar Z. Elizabeth Floyd Yongmei Yu Hisashi Fujioka Charles L. Hoppel Kathryn P. Belmont Christopher L. Axelrod John P. Kirwan |
| author_facet | Wagner S. Dantas Elizabeth R.M. Zunica Elizabeth C. Heintz Bolormaa Vandanmagsar Z. Elizabeth Floyd Yongmei Yu Hisashi Fujioka Charles L. Hoppel Kathryn P. Belmont Christopher L. Axelrod John P. Kirwan |
| author_sort | Wagner S. Dantas |
| collection | DOAJ |
| description | Abstract Background Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial‐targeted furazano[3,4‐b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet‐induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity. Methods Eighty‐week‐old male C57BL/6J mice with obesity were randomized to 10 weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w/w in high fat diet) treatment. Body weight and food intake were measured weekly. Body composition, muscle function, energy expenditure, locomotor activity, and glucose tolerance were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signalling, and mitochondrial structure and function. Results BAM15 decreased body weight (54.0 ± 2.0 vs. 42.3 ± 1.3 g, P < 0.001) which was attributable to increased energy expenditure (10.1 ± 0.1 vs. 11.3 ± 0.4 kcal/day, P < 0.001). BAM15 increased muscle mass (52.7 ± 0.4 vs. 59.4 ± 1.0%, P < 0.001), strength (91.1 ± 1.3 vs. 124.9 ± 1.2 g, P < 0.0001), and locomotor activity (347.0 ± 14.4 vs. 432.7 ± 32.0 m, P < 0.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (interleukin 6 and gp130, both P < 0.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control (PINK1‐ubiquitin binding and LC3II, P < 0.01), increased mitochondrial activity (citrate synthase and complex II activity, all P < 0.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble/soluble ratio, P < 0.0001) while limiting ER stress (decreased PERK signalling, P < 0.0001), apoptotic signalling (decreased cytochrome C release and Caspase‐3/9 activation, all P < 0.001), and muscle protein degradation (decreased 14‐kDa actin fragment insoluble/soluble ratio, P < 0.001). Conclusions Mitochondrial uncoupling by agents such as BAM15 may mitigate age‐related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity. |
| first_indexed | 2024-04-24T08:19:55Z |
| format | Article |
| id | doaj.art-04ea9ee21dc2491bba4d381201f55dcb |
| institution | Directory Open Access Journal |
| issn | 2190-5991 2190-6009 |
| language | English |
| last_indexed | 2024-04-24T08:19:55Z |
| publishDate | 2022-06-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj.art-04ea9ee21dc2491bba4d381201f55dcb2024-04-17T01:17:52ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092022-06-011331821183610.1002/jcsm.12982Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality controlWagner S. Dantas0Elizabeth R.M. Zunica1Elizabeth C. Heintz2Bolormaa Vandanmagsar3Z. Elizabeth Floyd4Yongmei Yu5Hisashi Fujioka6Charles L. Hoppel7Kathryn P. Belmont8Christopher L. Axelrod9John P. Kirwan10Integrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center Baton Rouge LA USAIntegrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center Baton Rouge LA USAIntegrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center Baton Rouge LA USAIntegrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center Baton Rouge LA USAUbiquitin Biology Laboratory Pennington Biomedical Research Center Baton Rouge LA USAUbiquitin Biology Laboratory Pennington Biomedical Research Center Baton Rouge LA USACryo‐Electron Microscopy Core Case Western Reserve University Cleveland OH USAIntegrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center Baton Rouge LA USAIntegrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center Baton Rouge LA USAIntegrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center Baton Rouge LA USAIntegrated Physiology and Molecular Medicine Laboratory Pennington Biomedical Research Center Baton Rouge LA USAAbstract Background Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial‐targeted furazano[3,4‐b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet‐induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity. Methods Eighty‐week‐old male C57BL/6J mice with obesity were randomized to 10 weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w/w in high fat diet) treatment. Body weight and food intake were measured weekly. Body composition, muscle function, energy expenditure, locomotor activity, and glucose tolerance were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signalling, and mitochondrial structure and function. Results BAM15 decreased body weight (54.0 ± 2.0 vs. 42.3 ± 1.3 g, P < 0.001) which was attributable to increased energy expenditure (10.1 ± 0.1 vs. 11.3 ± 0.4 kcal/day, P < 0.001). BAM15 increased muscle mass (52.7 ± 0.4 vs. 59.4 ± 1.0%, P < 0.001), strength (91.1 ± 1.3 vs. 124.9 ± 1.2 g, P < 0.0001), and locomotor activity (347.0 ± 14.4 vs. 432.7 ± 32.0 m, P < 0.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (interleukin 6 and gp130, both P < 0.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control (PINK1‐ubiquitin binding and LC3II, P < 0.01), increased mitochondrial activity (citrate synthase and complex II activity, all P < 0.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble/soluble ratio, P < 0.0001) while limiting ER stress (decreased PERK signalling, P < 0.0001), apoptotic signalling (decreased cytochrome C release and Caspase‐3/9 activation, all P < 0.001), and muscle protein degradation (decreased 14‐kDa actin fragment insoluble/soluble ratio, P < 0.001). Conclusions Mitochondrial uncoupling by agents such as BAM15 may mitigate age‐related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity.https://doi.org/10.1002/jcsm.12982SarcopeniaObesityAgeingBioenergeticsMitochondrial uncouplingBAM15 |
| spellingShingle | Wagner S. Dantas Elizabeth R.M. Zunica Elizabeth C. Heintz Bolormaa Vandanmagsar Z. Elizabeth Floyd Yongmei Yu Hisashi Fujioka Charles L. Hoppel Kathryn P. Belmont Christopher L. Axelrod John P. Kirwan Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control Journal of Cachexia, Sarcopenia and Muscle Sarcopenia Obesity Ageing Bioenergetics Mitochondrial uncoupling BAM15 |
| title | Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control |
| title_full | Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control |
| title_fullStr | Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control |
| title_full_unstemmed | Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control |
| title_short | Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control |
| title_sort | mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control |
| topic | Sarcopenia Obesity Ageing Bioenergetics Mitochondrial uncoupling BAM15 |
| url | https://doi.org/10.1002/jcsm.12982 |
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