Heart and neural crest derivative 2‐induced preservation of sympathetic neurons attenuates sarcopenia with aging
Abstract Background Sarcopenia, or age‐dependent decline in muscle force and power, impairs mobility, increasing the risk of falls, institutionalization, co‐morbidity, and premature death. The discovery of adrenoceptors, which mediate the effects of the sympathetic nervous system (SNS) neurotransmit...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Wiley
2021-02-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jcsm.12644 |
| _version_ | 1827280881237098496 |
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| author | Anna Carolina Zaia Rodrigues Zhong‐Min Wang María Laura Messi Henry Jacob Bonilla Liang Liu Willard M. Freeman Osvaldo Delbono |
| author_facet | Anna Carolina Zaia Rodrigues Zhong‐Min Wang María Laura Messi Henry Jacob Bonilla Liang Liu Willard M. Freeman Osvaldo Delbono |
| author_sort | Anna Carolina Zaia Rodrigues |
| collection | DOAJ |
| description | Abstract Background Sarcopenia, or age‐dependent decline in muscle force and power, impairs mobility, increasing the risk of falls, institutionalization, co‐morbidity, and premature death. The discovery of adrenoceptors, which mediate the effects of the sympathetic nervous system (SNS) neurotransmitter norepinephrine on specific tissues, sparked the development of sympathomimetics that have profound influence on skeletal muscle mass. However, chronic administration has serious side effects that preclude their use for muscle‐wasting conditions. Interventions that can adjust neurotransmitter release to changing physiological demands depend on understanding how the SNS affects neuromuscular transmission, muscle motor innervation, and muscle mass. Methods We examined age‐dependent expression of the heart and neural crest derivative 2 (Hand2), a critical transcription factor for SN maintenance, and we tested the possibility that inducing its expression exclusively in sympathetic neurons (SN) will prevent (i) motor denervation, (ii) impaired neuromuscular junction (NMJ) transmission, and (iii) loss of muscle mass and function in old mice. To test this hypothesis, we delivered a viral vector carrying Hand2 expression or an empty vector exclusively in SNs by vein injection in 16‐month‐old C57BL/6 mice that were sacrificed 6 months later. Techniques include RNA‐sequencing, real‐time PCR, genomic DNA methylation, viral vector construct, tissue immunohistochemistry, immunoblot, confocal microscopy, electrophysiology, and in vivo mouse physical performance. Results Hand2 expression declines throughout life, but inducing its expression increased (i) the number and size of SNs, (ii) muscle sympathetic innervation, (iii) muscle weight and force and whole‐body strength, (iv) myofiber size but not muscle fibre‐type composition, (v) NMJ transmission and nerve‐evoked muscle force, and (vi) motor innervation in old mice. Additionally, the SN controls a set of genes to reduce inflammation and to promote transcription factor activity, cell signalling, and synapse in the skeletal muscle. Hand2 DNA methylation may contribute, at least partially, to gene silencing. Conclusions Selective expression of Hand2 in the mouse SNs from middle age through old age increases muscle mass and force by (i) regulating skeletal muscle sympathetic and motor innervation; (ii) improving acetylcholine receptor stability and NMJ transmission; (iii) preventing inflammation and myofibrillar protein degradation; (iv) increasing autophagy; and (v) probably enhancing protein synthesis. |
| first_indexed | 2024-04-24T08:49:40Z |
| format | Article |
| id | doaj.art-464854ef47c14d1292faf48fce874759 |
| institution | Directory Open Access Journal |
| issn | 2190-5991 2190-6009 |
| language | English |
| last_indexed | 2024-04-24T08:49:40Z |
| publishDate | 2021-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj.art-464854ef47c14d1292faf48fce8747592024-04-16T12:30:20ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092021-02-011219110810.1002/jcsm.12644Heart and neural crest derivative 2‐induced preservation of sympathetic neurons attenuates sarcopenia with agingAnna Carolina Zaia Rodrigues0Zhong‐Min Wang1María Laura Messi2Henry Jacob Bonilla3Liang Liu4Willard M. Freeman5Osvaldo Delbono6Department of Internal Medicine, Section on Gerontology and Geriatric Medicine Wake Forest School of Medicine Winston‐Salem NC USADepartment of Internal Medicine, Section on Gerontology and Geriatric Medicine Wake Forest School of Medicine Winston‐Salem NC USADepartment of Internal Medicine, Section on Gerontology and Geriatric Medicine Wake Forest School of Medicine Winston‐Salem NC USADepartment of Internal Medicine, Section on Gerontology and Geriatric Medicine Wake Forest School of Medicine Winston‐Salem NC USAComprehensive Cancer Center Wake Forest School of Medicine Winston‐Salem NC USAReynolds Oklahoma Center on Aging Oklahoma City OK USADepartment of Internal Medicine, Section on Gerontology and Geriatric Medicine Wake Forest School of Medicine Winston‐Salem NC USAAbstract Background Sarcopenia, or age‐dependent decline in muscle force and power, impairs mobility, increasing the risk of falls, institutionalization, co‐morbidity, and premature death. The discovery of adrenoceptors, which mediate the effects of the sympathetic nervous system (SNS) neurotransmitter norepinephrine on specific tissues, sparked the development of sympathomimetics that have profound influence on skeletal muscle mass. However, chronic administration has serious side effects that preclude their use for muscle‐wasting conditions. Interventions that can adjust neurotransmitter release to changing physiological demands depend on understanding how the SNS affects neuromuscular transmission, muscle motor innervation, and muscle mass. Methods We examined age‐dependent expression of the heart and neural crest derivative 2 (Hand2), a critical transcription factor for SN maintenance, and we tested the possibility that inducing its expression exclusively in sympathetic neurons (SN) will prevent (i) motor denervation, (ii) impaired neuromuscular junction (NMJ) transmission, and (iii) loss of muscle mass and function in old mice. To test this hypothesis, we delivered a viral vector carrying Hand2 expression or an empty vector exclusively in SNs by vein injection in 16‐month‐old C57BL/6 mice that were sacrificed 6 months later. Techniques include RNA‐sequencing, real‐time PCR, genomic DNA methylation, viral vector construct, tissue immunohistochemistry, immunoblot, confocal microscopy, electrophysiology, and in vivo mouse physical performance. Results Hand2 expression declines throughout life, but inducing its expression increased (i) the number and size of SNs, (ii) muscle sympathetic innervation, (iii) muscle weight and force and whole‐body strength, (iv) myofiber size but not muscle fibre‐type composition, (v) NMJ transmission and nerve‐evoked muscle force, and (vi) motor innervation in old mice. Additionally, the SN controls a set of genes to reduce inflammation and to promote transcription factor activity, cell signalling, and synapse in the skeletal muscle. Hand2 DNA methylation may contribute, at least partially, to gene silencing. Conclusions Selective expression of Hand2 in the mouse SNs from middle age through old age increases muscle mass and force by (i) regulating skeletal muscle sympathetic and motor innervation; (ii) improving acetylcholine receptor stability and NMJ transmission; (iii) preventing inflammation and myofibrillar protein degradation; (iv) increasing autophagy; and (v) probably enhancing protein synthesis.https://doi.org/10.1002/jcsm.12644Skeletal muscleNeuromuscular junctionDenervationSarcopeniaSympathetic nervous systemAging |
| spellingShingle | Anna Carolina Zaia Rodrigues Zhong‐Min Wang María Laura Messi Henry Jacob Bonilla Liang Liu Willard M. Freeman Osvaldo Delbono Heart and neural crest derivative 2‐induced preservation of sympathetic neurons attenuates sarcopenia with aging Journal of Cachexia, Sarcopenia and Muscle Skeletal muscle Neuromuscular junction Denervation Sarcopenia Sympathetic nervous system Aging |
| title | Heart and neural crest derivative 2‐induced preservation of sympathetic neurons attenuates sarcopenia with aging |
| title_full | Heart and neural crest derivative 2‐induced preservation of sympathetic neurons attenuates sarcopenia with aging |
| title_fullStr | Heart and neural crest derivative 2‐induced preservation of sympathetic neurons attenuates sarcopenia with aging |
| title_full_unstemmed | Heart and neural crest derivative 2‐induced preservation of sympathetic neurons attenuates sarcopenia with aging |
| title_short | Heart and neural crest derivative 2‐induced preservation of sympathetic neurons attenuates sarcopenia with aging |
| title_sort | heart and neural crest derivative 2 induced preservation of sympathetic neurons attenuates sarcopenia with aging |
| topic | Skeletal muscle Neuromuscular junction Denervation Sarcopenia Sympathetic nervous system Aging |
| url | https://doi.org/10.1002/jcsm.12644 |
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