Key result
Selective homozygous lipin1 deficiency in skeletal muscle increased proapoptotic and necroptotic factors, membrane disruptions, and decreased muscle force compared to wild-type mice.
Why the study?
Mutations in lipin1 commonly cause massive rhabdomyolysis in children, but the molecular mechanisms regulating myofiber death caused by lipin1 deficiency are not fully understood.
In a mouse model, lipin1 deficiency in skeletal muscle leads to myofiber death and dysfunction associated with a loss of membrane integrity, providing insight into the mechanisms of massive rhabdomyolysis.
Membrane disruption associates lipin1 loss with myofiber apoptosis/necroptosis and force decline; leaves open human therapeutic targeting.
Mutations in lipin1 are suggested to be a common cause of massive rhabdomyolysis episodes in children; however, the molecular mechanisms involved in the regulation of myofiber death caused by the absence of lipin1 are not fully understood. Loss of membrane integrity is considered as an effective inducer of cell death in muscular dystrophy. In this study, we utilized a mouse line with selective homozygous lipin1 deficiency in the skeletal muscle (Lipin1Myf5cKO) to determine the role of compromised membrane integrity in the myofiber death in lipin1-deficient muscles. We found that Lipin1Myf5cKO muscles had significantly elevated proapoptotic factors (Bax, Bak, and cleaved caspase-9) and necroptotic proteins such as RIPK1, RIPK3, and MLKL compared with WT mice. Moreover, Lipin1Myf5cKO muscle had significantly higher membrane disruptions, as evidenced by increased IgG staining and elevated uptake of Evans Blue Dye (EBD) and increased serum creatine kinase activity in Lipin1Myf5cKO muscle fibers. EBD-positive fibers were strongly colocalized with apoptotic or necroptotic myofibers, suggesting an association between compromised plasma membrane integrity and cell death pathways. We further show that the absence of lipin1 leads to a significant decrease in the absolute and specific muscle force (normalized to muscle mass). Our work indicates that apoptosis and necroptosis are associated with a loss of membrane integrity in Lipin1Myf5cKO muscle and that myofiber death and dysfunction may cause a decrease in contractile force.
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Sattiraju et al. (2020) studied Lipin1 deficiency. Selective homozygous lipin1 deficiency vs. Wild-type mice was evaluated on Myofiber death, membrane integrity, and muscle force. Selective homozygous lipin1 deficiency in skeletal muscle increased proapoptotic and necroptotic factors, membrane disruptions, and decreased muscle force compared to wild-type mice.
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