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New Findings: Hindlimb Unloading Causes Nucleocytoplasmic Ca 2+ Overload and DNA Damage in Skeletal Muscle.
- Source :
-
Cells [Cells] 2023 Apr 03; Vol. 12 (7). Date of Electronic Publication: 2023 Apr 03. - Publication Year :
- 2023
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Abstract
- Disuse atrophy of skeletal muscle is associated with a severe imbalance in cellular Ca <superscript>2+</superscript> homeostasis and marked increase in nuclear apoptosis. Nuclear Ca <superscript>2+</superscript> is involved in the regulation of cellular Ca <superscript>2+</superscript> homeostasis. However, it remains unclear whether nuclear Ca <superscript>2+</superscript> levels change under skeletal muscle disuse conditions, and whether changes in nuclear Ca <superscript>2+</superscript> levels are associated with nuclear apoptosis. In this study, changes in Ca <superscript>2+</superscript> levels, Ca <superscript>2+</superscript> transporters, and regulatory factors in the nucleus of hindlimb unloaded rat soleus muscle were examined to investigate the effects of disuse on nuclear Ca <superscript>2+</superscript> homeostasis and apoptosis. Results showed that, after hindlimb unloading, the nuclear envelope Ca <superscript>2+</superscript> levels ([Ca <superscript>2+</superscript> ] <subscript>NE</subscript> ) and nucleocytoplasmic Ca <superscript>2+</superscript> levels ([Ca <superscript>2+</superscript> ] <subscript>NC</subscript> ) increased by 78% ( p < 0.01) and 106% ( p < 0.01), respectively. The levels of Ca <superscript>2+</superscript> -ATPase type 2 (Ca <superscript>2+</superscript> -ATPase2), Ryanodine receptor 1 (RyR1), Inositol 1,4,5-tetrakisphosphate receptor 1 (IP <subscript>3</subscript> R1), Cyclic ADP ribose hydrolase (CD38) and Inositol 1,4,5-tetrakisphosphate (IP <subscript>3</subscript> ) increased by 470% ( p < 0.001), 94% ( p < 0.05), 170% ( p < 0.001), 640% ( p < 0.001) and 12% ( p < 0.05), respectively, and the levels of Na <superscript>+</superscript> /Ca <superscript>2+</superscript> exchanger 3 (NCX3), Ca <superscript>2+</superscript> /calmodulin dependent protein kinase II (CaMK II) and Protein kinase A (PKA) decreased by 54% ( p < 0.001), 33% ( p < 0.05) and 5% ( p > 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 <superscript>2+</superscript> uptake from cytoplasm is involved in the increase in [Ca <superscript>2+</superscript> ] <subscript>NE</subscript> after hindlimb unloading. Moreover, the increase in [Ca <superscript>2+</superscript> ] <subscript>NC</subscript> is attributed to increased Ca <superscript>2+</superscript> release into nucleocytoplasm and weakened Ca <superscript>2+</superscript> uptake from nucleocytoplasm. DNase X is activated due to elevated [Ca <superscript>2+</superscript> ] <subscript>NC</subscript> , leading to DNA fragmentation in myonucleus, ultimately initiating myonuclear apoptosis. Nucleocytoplasmic Ca <superscript>2+</superscript> overload may contribute to the increased incidence of myonuclear apoptosis in disused skeletal muscle.
Details
- Language :
- English
- ISSN :
- 2073-4409
- Volume :
- 12
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Cells
- Publication Type :
- Academic Journal
- Accession number :
- 37048150
- Full Text :
- https://doi.org/10.3390/cells12071077