SLC25A12 mitigates mitochondrial dysfunction in myoblast senescence, and alleviates cuproptosis-related changes under
Shengwei Wang1, Weigen Wu2,3, Hua Yin1
1Department of Geriatrics, The First Affiliated Hospital, Sun Yat-sen University, No.58 Zhongshan Er Road, Guangzhou, Guangdong Province, 510080, P.R. China.
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.
