New Findings: Hindlimb Unloading Causes Nucleocytoplasmic Ca<sup>2+</sup> Overload and DNA Damage in Skeletal Muscle
Disuse atrophy of skeletal muscle is associated with a severe imbalance in cellular Ca<sup>2+</sup> homeostasis and marked increase in nuclear apoptosis. Nuclear Ca<sup>2+</sup> is involved in the regulation of cellular Ca<sup>2+</sup> homeostasis. However, it rem...
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MDPI AG
2023-04-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/12/7/1077 |
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| author | Huajian Yang Huiping Wang Fangyang Pan Yuxi Guo Liqi Cao Wenjing Yan Yunfang Gao |
| author_facet | Huajian Yang Huiping Wang Fangyang Pan Yuxi Guo Liqi Cao Wenjing Yan Yunfang Gao |
| author_sort | Huajian Yang |
| collection | DOAJ |
| description | Disuse atrophy of skeletal muscle is associated with a severe imbalance in cellular Ca<sup>2+</sup> homeostasis and marked increase in nuclear apoptosis. Nuclear Ca<sup>2+</sup> is involved in the regulation of cellular Ca<sup>2+</sup> homeostasis. However, it remains unclear whether nuclear Ca<sup>2+</sup> levels change under skeletal muscle disuse conditions, and whether changes in nuclear Ca<sup>2+</sup> levels are associated with nuclear apoptosis. In this study, changes in Ca<sup>2+</sup> levels, Ca<sup>2+</sup> transporters, and regulatory factors in the nucleus of hindlimb unloaded rat soleus muscle were examined to investigate the effects of disuse on nuclear Ca<sup>2+</sup> homeostasis and apoptosis. Results showed that, after hindlimb unloading, the nuclear envelope Ca<sup>2+</sup> levels ([Ca<sup>2+</sup>]<sub>NE</sub>) and nucleocytoplasmic Ca<sup>2+</sup> levels ([Ca<sup>2+</sup>]<sub>NC</sub>) increased by 78% (<i>p</i> < 0.01) and 106% (<i>p</i> < 0.01), respectively. The levels of Ca<sup>2+</sup>-ATPase type 2 (Ca<sup>2+</sup>-ATPase2), Ryanodine receptor 1 (RyR1), Inositol 1,4,5-tetrakisphosphate receptor 1 (IP<sub>3</sub>R1), Cyclic ADP ribose hydrolase (CD38) and Inositol 1,4,5-tetrakisphosphate (IP<sub>3</sub>) increased by 470% (<i>p</i> < 0.001), 94% (<i>p</i> < 0.05), 170% (<i>p</i> < 0.001), 640% (<i>p</i> < 0.001) and 12% (<i>p</i> < 0.05), respectively, and the levels of Na<sup>+</sup>/Ca<sup>2+</sup> exchanger 3 (NCX3), Ca<sup>2+</sup>/calmodulin dependent protein kinase II (CaMK II) and Protein kinase A (PKA) decreased by 54% (<i>p</i> < 0.001), 33% (<i>p</i> < 0.05) and 5% (<i>p</i> > 0.05), respectively. In addition, DNase X is mainly localized in the myonucleus and its activity is elevated after hindlimb unloading. Overall, our results suggest that enhanced Ca<sup>2+</sup> uptake from cytoplasm is involved in the increase in [Ca<sup>2+</sup>]<sub>NE</sub> after hindlimb unloading. Moreover, the increase in [Ca<sup>2+</sup>]<sub>NC</sub> is attributed to increased Ca<sup>2+</sup> release into nucleocytoplasm and weakened Ca<sup>2+</sup> uptake from nucleocytoplasm. DNase X is activated due to elevated [Ca<sup>2+</sup>]<sub>NC</sub>, leading to DNA fragmentation in myonucleus, ultimately initiating myonuclear apoptosis. Nucleocytoplasmic Ca<sup>2+</sup> overload may contribute to the increased incidence of myonuclear apoptosis in disused skeletal muscle. |
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| language | English |
| last_indexed | 2024-03-11T05:40:20Z |
| publishDate | 2023-04-01 |
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| series | Cells |
| spelling | doaj.art-eeda3e667e004fb583662f16de4886532023-11-17T16:28:58ZengMDPI AGCells2073-44092023-04-01127107710.3390/cells12071077New Findings: Hindlimb Unloading Causes Nucleocytoplasmic Ca<sup>2+</sup> Overload and DNA Damage in Skeletal MuscleHuajian Yang0Huiping Wang1Fangyang Pan2Yuxi Guo3Liqi Cao4Wenjing Yan5Yunfang Gao6Shaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi’an 710069, ChinaShaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi’an 710069, ChinaShaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi’an 710069, ChinaShaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi’an 710069, ChinaShaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi’an 710069, ChinaShaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi’an 710069, ChinaShaanxi Key Laboratory for Animal Conservation, College of Life Sciences, Northwest University, Xi’an 710069, ChinaDisuse atrophy of skeletal muscle is associated with a severe imbalance in cellular Ca<sup>2+</sup> homeostasis and marked increase in nuclear apoptosis. Nuclear Ca<sup>2+</sup> is involved in the regulation of cellular Ca<sup>2+</sup> homeostasis. However, it remains unclear whether nuclear Ca<sup>2+</sup> levels change under skeletal muscle disuse conditions, and whether changes in nuclear Ca<sup>2+</sup> levels are associated with nuclear apoptosis. In this study, changes in Ca<sup>2+</sup> levels, Ca<sup>2+</sup> transporters, and regulatory factors in the nucleus of hindlimb unloaded rat soleus muscle were examined to investigate the effects of disuse on nuclear Ca<sup>2+</sup> homeostasis and apoptosis. Results showed that, after hindlimb unloading, the nuclear envelope Ca<sup>2+</sup> levels ([Ca<sup>2+</sup>]<sub>NE</sub>) and nucleocytoplasmic Ca<sup>2+</sup> levels ([Ca<sup>2+</sup>]<sub>NC</sub>) increased by 78% (<i>p</i> < 0.01) and 106% (<i>p</i> < 0.01), respectively. The levels of Ca<sup>2+</sup>-ATPase type 2 (Ca<sup>2+</sup>-ATPase2), Ryanodine receptor 1 (RyR1), Inositol 1,4,5-tetrakisphosphate receptor 1 (IP<sub>3</sub>R1), Cyclic ADP ribose hydrolase (CD38) and Inositol 1,4,5-tetrakisphosphate (IP<sub>3</sub>) increased by 470% (<i>p</i> < 0.001), 94% (<i>p</i> < 0.05), 170% (<i>p</i> < 0.001), 640% (<i>p</i> < 0.001) and 12% (<i>p</i> < 0.05), respectively, and the levels of Na<sup>+</sup>/Ca<sup>2+</sup> exchanger 3 (NCX3), Ca<sup>2+</sup>/calmodulin dependent protein kinase II (CaMK II) and Protein kinase A (PKA) decreased by 54% (<i>p</i> < 0.001), 33% (<i>p</i> < 0.05) and 5% (<i>p</i> > 0.05), respectively. In addition, DNase X is mainly localized in the myonucleus and its activity is elevated after hindlimb unloading. Overall, our results suggest that enhanced Ca<sup>2+</sup> uptake from cytoplasm is involved in the increase in [Ca<sup>2+</sup>]<sub>NE</sub> after hindlimb unloading. Moreover, the increase in [Ca<sup>2+</sup>]<sub>NC</sub> is attributed to increased Ca<sup>2+</sup> release into nucleocytoplasm and weakened Ca<sup>2+</sup> uptake from nucleocytoplasm. DNase X is activated due to elevated [Ca<sup>2+</sup>]<sub>NC</sub>, leading to DNA fragmentation in myonucleus, ultimately initiating myonuclear apoptosis. Nucleocytoplasmic Ca<sup>2+</sup> overload may contribute to the increased incidence of myonuclear apoptosis in disused skeletal muscle.https://www.mdpi.com/2073-4409/12/7/1077skeletal musclehindlimb unloadingnuclear Ca<sup>2+</sup> regulationnuclear apoptosis |
| spellingShingle | Huajian Yang Huiping Wang Fangyang Pan Yuxi Guo Liqi Cao Wenjing Yan Yunfang Gao New Findings: Hindlimb Unloading Causes Nucleocytoplasmic Ca<sup>2+</sup> Overload and DNA Damage in Skeletal Muscle Cells skeletal muscle hindlimb unloading nuclear Ca<sup>2+</sup> regulation nuclear apoptosis |
| title | New Findings: Hindlimb Unloading Causes Nucleocytoplasmic Ca<sup>2+</sup> Overload and DNA Damage in Skeletal Muscle |
| title_full | New Findings: Hindlimb Unloading Causes Nucleocytoplasmic Ca<sup>2+</sup> Overload and DNA Damage in Skeletal Muscle |
| title_fullStr | New Findings: Hindlimb Unloading Causes Nucleocytoplasmic Ca<sup>2+</sup> Overload and DNA Damage in Skeletal Muscle |
| title_full_unstemmed | New Findings: Hindlimb Unloading Causes Nucleocytoplasmic Ca<sup>2+</sup> Overload and DNA Damage in Skeletal Muscle |
| title_short | New Findings: Hindlimb Unloading Causes Nucleocytoplasmic Ca<sup>2+</sup> Overload and DNA Damage in Skeletal Muscle |
| title_sort | new findings hindlimb unloading causes nucleocytoplasmic ca sup 2 sup overload and dna damage in skeletal muscle |
| topic | skeletal muscle hindlimb unloading nuclear Ca<sup>2+</sup> regulation nuclear apoptosis |
| url | https://www.mdpi.com/2073-4409/12/7/1077 |
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