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RIP1 Regulates Mitochondrial Fission during Skeletal Muscle Ischemia Reperfusion Injury
Yu Cao1, Shunli Chen1, Xiangqing Xiong1
1Department of Anesthesiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province, China.
Background:
Dynamin related protein-1 (Drp1)-mediated mitochondrial fission relates to ischemia reperfusion (IR) injury, and its association with necroptosis is implied. We hypothesized that receptor-interacting protein 1 (RIP1), a key kinase in necroptosis, acted as an upstream of Drp1-mediated mitochondrial fission during skeletal muscle IR.
Methods:
Thirty rats were randomized into the SM, IR, NI, MI, and DI group (n = 6). The rats in the SM group were shamly operated, and those in the IR group were subjected to 4-hour ischemia of the right hindlimb that was followed by 4-hour reperfusion. Intraperitoneal administration of Nec-1 1 mg/kg, Mdivi-1 1.2 mg/kg and same volume of DMSO were given before ischemia in the NI, MI and DI groups, respectively. Upon reperfusion, the soleus muscles were harvested to determine morphological changes and the expression of RIP1, total Drp1 and p-Drp1 (Ser616). Moreover, the muscular oxidative stress indicators and plasma muscle damage biomarkers were detected.
Results:
IR led to impaired histopathological structures and mitochondrial fragmentation in the soleus muscle tissue, accompanied with increased muscular oxidative stress and muscle injury biomarkers, which could be similarly alleviated by Mdivi-1 and Nec-1 (p < 0.05). RIP1 and p-Drp1 (Ser616) protein levels were significantly upregulated in the soleus muscle subjected to IR injury, this upregulation was attenuated in the NI group, and Mdivi-1 downregulated the protein expression of p-Drp1 (Ser616) but not of RIP1 (p < 0.05).
Conclusion:
RIP1 functions as an upstream of Drp1-mediated mitochondrial fission in the execution of necroptosis during skeletal muscle IR.
Insights
Receptor-interacting protein 1 (RIP1) acts upstream of dynamin-related protein-1 (Drp1) in skeletal muscle ischemia-reperfusion (IR) injury. Inhibiting RIP1 or Drp1 reduces muscle damage and mitochondrial fragmentation during IR.
Area of Science:
- Muscle Physiology
- Cellular Biology
- Pathology
Background:
- Dynamin-related protein-1 (Drp1)-mediated mitochondrial fission is linked to ischemia-reperfusion (IR) injury.
- The role of necroptosis, particularly receptor-interacting protein 1 (RIP1) kinase, in this process is implied but not fully understood.
Purpose of the Study:
- To investigate the upstream role of RIP1 in Drp1-mediated mitochondrial fission during skeletal muscle IR.
- To determine the effects of RIP1 and Drp1 inhibition on muscle damage and oxidative stress.
Main Methods:
- Thirty rats were divided into sham-operated, IR, Nec-1 (RIP1 inhibitor), Mdivi-1 (Drp1 inhibitor), and vehicle control groups.
- Soleus muscles were analyzed for histopathology, mitochondrial morphology, RIP1 and Drp1 (total and phosphorylated) expression, oxidative stress markers, and muscle damage biomarkers.
Main Results:
- Ischemia-reperfusion induced significant mitochondrial fragmentation, increased oxidative stress, and elevated muscle damage biomarkers in soleus muscles.
- Both Nec-1 and Mdivi-1 treatments attenuated these IR-induced detrimental effects.
- RIP1 and phosphorylated Drp1 (p-Drp1 Ser616) levels were upregulated post-IR, with Nec-1 attenuating RIP1 and p-Drp1, while Mdivi-1 only reduced p-Drp1.
Conclusions:
- Receptor-interacting protein 1 (RIP1) kinase functions upstream of Drp1-mediated mitochondrial fission in the execution of necroptosis during skeletal muscle IR injury.
- Targeting RIP1 or Drp1 may offer therapeutic strategies for mitigating skeletal muscle IR injury.
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