Loss of FAM210A in Satellite Cell Drives Mitochondrial Dysfunction and Muscle Weakness in Experimental Peripheral Artery Disease
Authors: Dong Gengfu , Li Yufen , Lackey Jacob , Yang Qingping , Thome Trace , Yue Feng , Ryan Terence 
Published: May 2024

Introduction: Peripheral artery disease (PAD) affects approximately 200 million people globally. Chronic limb-threatening ischemia (CLTI) represents the most advanced clinical phenotype of PAD. Mitochondrial metabolism defects are apparent in the satellite cells of CLTI patients, and the muscle regeneration process demands increased energy, with satellite cell mitochondrial metabolism and dynamics playing a crucial role. However, our current understanding of the role of satellite cells and muscle regeneration in PAD pathology is notably inadequate. Recent studies have shown that the absence of FAM210A, a newly identified mitochondrial protein, can trigger morphological and energetic abnormalities in mitochondria, resulting in muscle function deterioration and promoting muscle wasting. Given the impaired mitochondrial function in satellite cells in CLTI patients and the heightened energy demand regulated by mitochondrial dynamics during muscle regeneration in satellite cell, it is therefore essential to exploring the role of FAM210A in satellite cells in CLTI limb pathology. The objective of this study was to investigate the impact of the loss of FAM210A in satellite cells in mice with experimental PAD. Methods: Male and female conditional FAM210A satellite cell knock out (FAM210ASCKO) and FAM210A floxed (FAM210Afl/fl) mice (N=3-5) were used for this project. Femoral artery ligation surgery was performed to induce PAD. Tamoxifen was administered for 5 days intraperitoneally one week prior to the surgery. Mice were euthanized twenty-eight days after surgery. Outcome measures included limb perfusion assessment, muscle weight, muscle force production, and mitochondrial respiration. Results: FAM210ASCKO mice had significantly decreased muscle mass of the tibialis anterior and extensor digitorum longus ( p<0.0001 and p=0.0004 respectively). More importantly, maximal muscle force with in-situ contraction in tibialis anterior was significantly lower in FAM210ASCKO mice compared to FAM210Afl/fl mice (FAM210Afl/fl mice: 1085.16 ± 331.08 mN; FAM210ASCKO mice: 430.77 ± 467.91 mN; p=0.0139). Furthermore, analysis of mitochondrial oxidative phosphorylation (OXPHOS) revealed that FAM210ASCKO mice had a significant reduction compared to FAM210Afl/fl mice (48%) in skeletal muscle mitochondrial bioenergetic function at various levels of energy demand mimicking from resting to maximal exercise when carbohydrate was used to energize mitochondria ( p=0.034). Importantly, the analysis of mitochondrial membrane potential consistently reveals a substantial reduction in FAM210ASCKO mice compared to FAM210Afl/fl mice, which can partially explain the diminished mitochondrial bioenergetic function observed in ischemic FAM210ASCKO mice. Conclusion: The results of this study indicate that the loss of FAM210A in satellite cells exacerbates ischemic muscle pathology evidenced by muscle weakness and mitochondrial failure in FAM210ASCKO mice with PAD. Future work is needed to elucidate the mechanisms by which FAM210A regulate ischemic satellite cell function and the therapeutic potential of preventing ischemia-induced loss of FAM210A in PAD.

This study was supported by National Institutes of Health (NIH) grant R01-HL149704 (to Dr Ryan). Mr Thome was supported by NIH grant F31-DK128920.

This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.