Apobec2 deficiency causes mitochondrial defects and mitophagy in skeletal muscle
Yusuke Sato1, Hideaki Ohtsubo2, Naohiro Nihei1
1Department of Agrobiology and Bioresources, Utsunomiya University, Tochigi, Japan.
Abstract:
Apobec2 is a member of the activation-induced deaminase/apolipoprotein B mRNA editing enzyme catalytic polypeptide cytidine deaminase family expressed in differentiated skeletal and cardiac muscle. We previously reported that Apobec2 deficiency in mice leads to a shift in muscle fiber type, myopathy, and diminished muscle mass. However, the mechanisms of myopathy caused by Apobec2 deficiency and its physiologic functions are unclear. Here we show that, although Apobec2 localizes to the sarcomeric Z-lines in mouse tissue and cultured myotubes, the sarcomeric structure is not affected in Apobec2-deficient muscle. In contrast, electron microscopy reveals enlarged mitochondria and mitochondria engulfed by autophagic vacuoles, suggesting that Apobec2 deficiency causes mitochondrial defects leading to increased mitophagy in skeletal muscle. Indeed, Apobec2 deficiency results in increased reactive oxygen species generation and depolarized mitochondria, leading to mitophagy as a defensive response. Furthermore, the exercise capacity of Apobec2-/- mice is impaired, implying Apobec2 deficiency results in ongoing muscle dysfunction. The presence of rimmed vacuoles in myofibers from 10-mo-old mice suggests that the chronic muscle damage impairs normal autophagy. We conclude that Apobec2 deficiency causes mitochondrial defects that increase muscle mitophagy, leading to myopathy and atrophy. Our findings demonstrate that Apobec2 is required for mitochondrial homeostasis to maintain normal skeletal muscle function.-Sato, Y., Ohtsubo, H., Nihei, N., Kaneko, T., Sato, Y., Adachi, S.-I., Kondo, S., Nakamura, M., Mizunoya, W., Iida, H., Tatsumi, R., Rada, C., Yoshizawa, F. Apobec2 deficiency causes mitochondrial defects and mitophagy in skeletal muscle.
Insights
Apobec2 deficiency causes mitochondrial defects, leading to increased mitophagy and impaired skeletal muscle function in mice. This research highlights Apobec2
Area of Science:
- Muscle physiology and mitochondrial biology.
- Cellular mechanisms of myopathy.
- Biochemistry of cytidine deaminases.
Background:
- Apobec2 (activation-induced deaminase/apolipoprotein B mRNA editing enzyme catalytic polypeptide) is expressed in skeletal and cardiac muscle.
- Apobec2 deficiency in mice causes muscle fiber type shifts, myopathy, and reduced muscle mass.
- The precise mechanisms underlying Apobec2 deficiency-induced myopathy and its physiological roles remain unclear.
Purpose of the Study:
- To elucidate the mechanisms of myopathy in Apobec2-deficient mice.
- To investigate the physiological functions of Apobec2 in skeletal muscle.
- To determine the role of Apobec2 in mitochondrial homeostasis and muscle function.
Main Methods:
- Analysis of Apobec2 localization in mouse tissues and cultured myotubes.
- Electron microscopy to examine sarcomeric structure and mitochondrial morphology.
- Assessment of reactive oxygen species (ROS) generation and mitochondrial membrane potential.
- Evaluation of exercise capacity in Apobec2-deficient mice.
- Histological examination for myopathy markers like rimmed vacuoles.
Main Results:
- Apobec2 localizes to sarcomeric Z-lines, but its absence does not affect sarcomeric structure.
- Apobec2 deficiency leads to enlarged mitochondria and increased autophagic vacuoles engulfing mitochondria (mitophagy).
- Mitochondria in deficient muscle exhibit increased ROS production and depolarization, triggering mitophagy.
- Apobec2-deficient mice show impaired exercise capacity and chronic muscle damage with rimmed vacuoles.
Conclusions:
- Apobec2 deficiency causes mitochondrial dysfunction, characterized by increased mitophagy, leading to myopathy and muscle atrophy.
- Apobec2 is essential for maintaining mitochondrial homeostasis in skeletal muscle.
- These findings reveal a critical role for Apobec2 in preventing muscle disease through mitochondrial quality control.
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