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Background <p>Sarcopenia is an age-related muscle wasting condition that currently lacks specific diagnostic biomarkers and effective treatments. This study aimed to identify mitochondria-related biomarkers for sarcopenia via integrated multi-omics.</p> Methods <p>Human transcriptomic datasets and machine learning algorithms were integrated to screen core mitochondria-related biomarkers for sarcopenia. In vivo validation was performed utilizing 24-month-old naturally aging mice exhibiting sarcopenia features. In vitro, SLC25A12 was either overexpressed or silenced in C2C12 myoblasts subjected to D-galactose-induced senescence or copper stress. Pathophysiological changes and molecular mechanisms were subsequently evaluated via immunofluorescence, mitochondrial functional assays, and Western blotting. Additionally, single-cell RNA sequencing combined with a Geneformer model was employed in MuSCs for in silico perturbation analysis.</p> Results <p>Transcriptomic and machine learning analyses identified SLC25A12 as a core mitochondria-related gene, exhibiting consistent downregulation in both human sarcopenia cohorts and 24-month-old aging mice. In vitro, SLC25A12 overexpression in C2C12 myoblasts significantly ameliorated senescence induced by D-galactose and preserved mitochondrial function, highlighted by increased EdU incorporation and restored membrane potential. Furthermore, under copper stress, elevated SLC25A12 levels effectively alleviated cuproptosis-related alterations, including restricting mitochondrial copper overload, suppressing DLAT oligomerization, and partially restoring impaired EdU incorporation. Conversely, SLC25A12 knockdown consistently aggravated these phenotypes in both models. Notably, in silico Geneformer-based perturbation of SLC25A12 in MuSCs predicted its regulatory roles in cellular senescence, mitochondrial function, and copper homeostasis. In vitro experiments further demonstrated that SLC25A12 overexpression partially restored suppressed PI3K/AKT signaling under senescent stress conditions.</p> Conclusion <p>SLC25A12 expression ameliorates myoblast senescence and mitochondrial dysfunction, while also attenuating cuproptosis-related changes under copper stress. SLC25A12 knockdown exacerbates these phenotypes. Taken together, SLC25A12 represents a potential regulator and therapeutic target for skeletal muscle aging.</p>

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SLC25A12 mitigates mitochondrial dysfunction in myoblast senescence, and alleviates cuproptosis-related changes under copper stress

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月3日

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  • Shengwei Wang,
  • Weigen Wu,
  • Hua Yin,
  • Qiushuo Chen,
  • Ling Zhang,
  • Wen He

摘要

Background

Sarcopenia is an age-related muscle wasting condition that currently lacks specific diagnostic biomarkers and effective treatments. This study aimed to identify mitochondria-related biomarkers for sarcopenia via integrated multi-omics.

Methods

Human transcriptomic datasets and machine learning algorithms were integrated to screen core mitochondria-related biomarkers for sarcopenia. In vivo validation was performed utilizing 24-month-old naturally aging mice exhibiting sarcopenia features. In vitro, SLC25A12 was either overexpressed or silenced in C2C12 myoblasts subjected to D-galactose-induced senescence or copper stress. Pathophysiological changes and molecular mechanisms were subsequently evaluated via immunofluorescence, mitochondrial functional assays, and Western blotting. Additionally, single-cell RNA sequencing combined with a Geneformer model was employed in MuSCs for in silico perturbation analysis.

Results

Transcriptomic and machine learning analyses identified SLC25A12 as a core mitochondria-related gene, exhibiting consistent downregulation in both human sarcopenia cohorts and 24-month-old aging mice. In vitro, SLC25A12 overexpression in C2C12 myoblasts significantly ameliorated senescence induced by D-galactose and preserved mitochondrial function, highlighted by increased EdU incorporation and restored membrane potential. Furthermore, under copper stress, elevated SLC25A12 levels effectively alleviated cuproptosis-related alterations, including restricting mitochondrial copper overload, suppressing DLAT oligomerization, and partially restoring impaired EdU incorporation. Conversely, SLC25A12 knockdown consistently aggravated these phenotypes in both models. Notably, in silico Geneformer-based perturbation of SLC25A12 in MuSCs predicted its regulatory roles in cellular senescence, mitochondrial function, and copper homeostasis. In vitro experiments further demonstrated that SLC25A12 overexpression partially restored suppressed PI3K/AKT signaling under senescent stress conditions.

Conclusion

SLC25A12 expression ameliorates myoblast senescence and mitochondrial dysfunction, while also attenuating cuproptosis-related changes under copper stress. SLC25A12 knockdown exacerbates these phenotypes. Taken together, SLC25A12 represents a potential regulator and therapeutic target for skeletal muscle aging.