H19X‐encoded miR‐322(424)/miR‐503 regulates muscle mass by targeting translation initiation factors
Abstract Background Skeletal muscle atrophy is a debilitating complication of many chronic diseases, disuse conditions, and ageing. Genome‐wide gene expression analyses have identified that elevated levels of microRNAs encoded by the H19X locus are among the most significant changes in skeletal musc...
| Main Authors: | , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2021-12-01
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| Series: | Journal of Cachexia, Sarcopenia and Muscle |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/jcsm.12827 |
| _version_ | 1798032651042422784 |
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| author | Rui Liang Xiaopeng Shen Fan Wang Xin Wang Alex DesJarlais Anam Syed Raymond Saba Zhi Tan Fang Yu Xuan Ji Shreesti Shrestha Yinghong Ren Jin Yang Yoonjung Park Robert J. Schwartz Benjamin Soibam Bradley K. McConnell M. David Stewart Ashok Kumar Yu Liu |
| author_facet | Rui Liang Xiaopeng Shen Fan Wang Xin Wang Alex DesJarlais Anam Syed Raymond Saba Zhi Tan Fang Yu Xuan Ji Shreesti Shrestha Yinghong Ren Jin Yang Yoonjung Park Robert J. Schwartz Benjamin Soibam Bradley K. McConnell M. David Stewart Ashok Kumar Yu Liu |
| author_sort | Rui Liang |
| collection | DOAJ |
| description | Abstract Background Skeletal muscle atrophy is a debilitating complication of many chronic diseases, disuse conditions, and ageing. Genome‐wide gene expression analyses have identified that elevated levels of microRNAs encoded by the H19X locus are among the most significant changes in skeletal muscles in a wide scope of human cachectic conditions. We have previously reported that the H19X locus is important for the establishment of striated muscle fate during embryogenesis. However, the role of H19X‐encoded microRNAs in regulating skeletal mass in adults is unknown. Methods We have created a transgenic mouse strain in which ectopic expression of miR‐322/miR‐503 is driven by the skeletal muscle‐specific muscle creatine kinase promoter. We also used an H19X mutant mouse strain in which transcription from the locus is interrupted by a gene trap. Animal phenotypes were analysed by standard histological methods. Underlying mechanisms were explored by using transcriptome profiling and validated in the two animal models and cultured myotubes. Results Our results demonstrate that the levels of H19X microRNAs are inversely related to postnatal skeletal muscle growth. Targeted overexpression of miR‐322/miR‐503 impeded skeletal muscle growth. The weight of gastrocnemius muscles of transgenic mice was only 54.5% of the counterparts of wild‐type littermates. By contrast, interruption of transcription from the H19X locus stimulates postnatal muscle growth by 14.4–14.9% and attenuates the loss of skeletal muscle mass in response to starvation by 12.8–21.0%. Impeded muscle growth was not caused by impaired IGF1/AKT/mTOR signalling or a hyperactive ubiquitin–proteasome system, instead accompanied by markedly dropped abundance of translation initiation factors in transgenic mice. miR‐322/miR‐503 directly targets eIF4E, eIF4G1, eIF4B, eIF2B5, and eIF3M. Conclusions Our study illustrates a novel pathway wherein H19X microRNAs regulate skeletal muscle growth and atrophy through regulating the abundance of translation initiation factors, thereby protein synthesis. The study highlights how translation initiation factors lie at the crux of multiple signalling pathways that control skeletal muscle mass. |
| first_indexed | 2024-04-11T20:16:20Z |
| format | Article |
| id | doaj.art-bd56645cb21b4cd6bfe0a9c549f489cf |
| institution | Directory Open Access Journal |
| issn | 2190-5991 2190-6009 |
| language | English |
| last_indexed | 2024-04-11T20:16:20Z |
| publishDate | 2021-12-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Cachexia, Sarcopenia and Muscle |
| spelling | doaj.art-bd56645cb21b4cd6bfe0a9c549f489cf2022-12-22T04:04:57ZengWileyJournal of Cachexia, Sarcopenia and Muscle2190-59912190-60092021-12-011262174218610.1002/jcsm.12827H19X‐encoded miR‐322(424)/miR‐503 regulates muscle mass by targeting translation initiation factorsRui Liang0Xiaopeng Shen1Fan Wang2Xin Wang3Alex DesJarlais4Anam Syed5Raymond Saba6Zhi Tan7Fang Yu8Xuan Ji9Shreesti Shrestha10Yinghong Ren11Jin Yang12Yoonjung Park13Robert J. Schwartz14Benjamin Soibam15Bradley K. McConnell16M. David Stewart17Ashok Kumar18Yu Liu19Department of Biology and Biochemistry University of Houston Houston TX USADepartment of Biology and Biochemistry University of Houston Houston TX USADepartment of Biology and Biochemistry University of Houston Houston TX USADepartment of Biology and Biochemistry University of Houston Houston TX USADepartment of Biology and Biochemistry University of Houston Houston TX USADepartment of Biology and Biochemistry University of Houston Houston TX USADepartment of Biology and Biochemistry University of Houston Houston TX USADepartment of Experimental Therapeutics University of Texas MD Anderson Cancer Center Houston TX USADepartment of Biology and Biochemistry University of Houston Houston TX USADepartment of Biology and Biochemistry University of Houston Houston TX USADepartment of Biology and Biochemistry University of Houston Houston TX USADepartment of Oncology Shangluo Central Hospital Shangluo Shaanxi Province ChinaDepartment of Oncology The First Affiliated Hospital of Xi'an Jiaotong University Xi'an Shaanxi Province ChinaDepartment of Health and Human Performance University of Houston Houston TX USADepartment of Biology and Biochemistry University of Houston Houston TX USADepartment of Computer Science and Engineering Technology University of Houston‐Downtown Houston TX USADepartment of Pharmacological & Pharmaceutical Sciences University of Houston Houston TX USADepartment of Biology and Biochemistry University of Houston Houston TX USADepartment of Pharmacological & Pharmaceutical Sciences University of Houston Houston TX USADepartment of Biology and Biochemistry University of Houston Houston TX USAAbstract Background Skeletal muscle atrophy is a debilitating complication of many chronic diseases, disuse conditions, and ageing. Genome‐wide gene expression analyses have identified that elevated levels of microRNAs encoded by the H19X locus are among the most significant changes in skeletal muscles in a wide scope of human cachectic conditions. We have previously reported that the H19X locus is important for the establishment of striated muscle fate during embryogenesis. However, the role of H19X‐encoded microRNAs in regulating skeletal mass in adults is unknown. Methods We have created a transgenic mouse strain in which ectopic expression of miR‐322/miR‐503 is driven by the skeletal muscle‐specific muscle creatine kinase promoter. We also used an H19X mutant mouse strain in which transcription from the locus is interrupted by a gene trap. Animal phenotypes were analysed by standard histological methods. Underlying mechanisms were explored by using transcriptome profiling and validated in the two animal models and cultured myotubes. Results Our results demonstrate that the levels of H19X microRNAs are inversely related to postnatal skeletal muscle growth. Targeted overexpression of miR‐322/miR‐503 impeded skeletal muscle growth. The weight of gastrocnemius muscles of transgenic mice was only 54.5% of the counterparts of wild‐type littermates. By contrast, interruption of transcription from the H19X locus stimulates postnatal muscle growth by 14.4–14.9% and attenuates the loss of skeletal muscle mass in response to starvation by 12.8–21.0%. Impeded muscle growth was not caused by impaired IGF1/AKT/mTOR signalling or a hyperactive ubiquitin–proteasome system, instead accompanied by markedly dropped abundance of translation initiation factors in transgenic mice. miR‐322/miR‐503 directly targets eIF4E, eIF4G1, eIF4B, eIF2B5, and eIF3M. Conclusions Our study illustrates a novel pathway wherein H19X microRNAs regulate skeletal muscle growth and atrophy through regulating the abundance of translation initiation factors, thereby protein synthesis. The study highlights how translation initiation factors lie at the crux of multiple signalling pathways that control skeletal muscle mass.https://doi.org/10.1002/jcsm.12827Skeletal muscle atrophyProtein synthesisH19XMicroRNAsmiR‐322miR‐424 |
| spellingShingle | Rui Liang Xiaopeng Shen Fan Wang Xin Wang Alex DesJarlais Anam Syed Raymond Saba Zhi Tan Fang Yu Xuan Ji Shreesti Shrestha Yinghong Ren Jin Yang Yoonjung Park Robert J. Schwartz Benjamin Soibam Bradley K. McConnell M. David Stewart Ashok Kumar Yu Liu H19X‐encoded miR‐322(424)/miR‐503 regulates muscle mass by targeting translation initiation factors Journal of Cachexia, Sarcopenia and Muscle Skeletal muscle atrophy Protein synthesis H19X MicroRNAs miR‐322 miR‐424 |
| title | H19X‐encoded miR‐322(424)/miR‐503 regulates muscle mass by targeting translation initiation factors |
| title_full | H19X‐encoded miR‐322(424)/miR‐503 regulates muscle mass by targeting translation initiation factors |
| title_fullStr | H19X‐encoded miR‐322(424)/miR‐503 regulates muscle mass by targeting translation initiation factors |
| title_full_unstemmed | H19X‐encoded miR‐322(424)/miR‐503 regulates muscle mass by targeting translation initiation factors |
| title_short | H19X‐encoded miR‐322(424)/miR‐503 regulates muscle mass by targeting translation initiation factors |
| title_sort | h19x encoded mir 322 424 mir 503 regulates muscle mass by targeting translation initiation factors |
| topic | Skeletal muscle atrophy Protein synthesis H19X MicroRNAs miR‐322 miR‐424 |
| url | https://doi.org/10.1002/jcsm.12827 |
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