Affiliation:
1. Laboratory of Mitochondria and Metabolism, West China Hospital of Sichuan University, Chengdu, China
Abstract
ABSTRACT
Purpose: Intensive care unit–acquired weakness (ICUAW) is a severe neuromuscular complication that frequently occurs in patients with sepsis. The precise molecular pathophysiology of mitochondrial calcium uptake 1 (MICU1) and mitochondrial calcium uniporter (MCU) in ICUAW has not been fully elucidated. Here, we speculate that ICUAW is associated with MICU1:MCU protein ratio–mediated mitochondrial calcium ([Ca2+]m) uptake dysfunction. Methods: Cecal ligation and perforation (CLP) was performed on C57BL/6J mice to induce sepsis. Sham-operated animals were used as controls. Lipopolysaccharide (LPS) (5 μg/mL) was used to induce inflammation in differentiated C2C12 myoblasts. Compound muscle action potential (CMAP) was detected using a biological signal acquisition system. Grip strength was measured using a grip-strength meter. Skeletal muscle inflammatory factors were detected using ELISA kits. The cross-sectional area (CSA) of the tibialis anterior (TA) muscle was detected by hematoxylin and eosin staining. Cytosolic calcium ([Ca2+]c) levels were measured using Fluo-4 AM. Adeno-associated virus (AAV) was injected into TA muscles for 4 weeks to overexpress MICU1 prophylactically. A lentivirus was used to infect C2C12 cells to increase MICU1 expression prophylactically. Findings: The results suggest that sepsis induces [Ca2+]m uptake disorder by reducing the MICU1:MCU protein ratio, resulting in skeletal muscle weakness and muscle fiber atrophy. However, MICU1 prophylactic overexpression reversed these effects by increasing the MICU1:MCU protein ratio. Conclusions: ICUAW is associated with impaired [Ca2+]m uptake caused by a decreased MICU1:MCU protein ratio. MICU1 overexpression improves sepsis-induced skeletal muscle weakness and atrophy by ameliorating the [Ca2+]m uptake disorder.
Publisher
Ovid Technologies (Wolters Kluwer Health)
Subject
Critical Care and Intensive Care Medicine,Emergency Medicine