Background: Mitochondrial injury develops in skeletal muscles during the
course of severe sepsis. Autophagy is a protein and organelle recycling
pathway which functions to degrade or recycle unnecessary, redundant, or
inefficient cellular components. No information is available regarding
the degree of sepsis-induced mitochondrial injury and autophagy in the
ventilatory and locomotor muscles. This study tests the hypotheses that
the locomotor muscles are more prone to sepsis-induced mitochondrial
injury, depressed biogenesis and autophagy induction compared with the
ventilatory muscles.
Methodology/Principal Findings: Adult male C57/Bl6 mice were injected
with i.p. phosphate buffered saline (PBS) or E. coli lipopolysaccharide
(LPS, 20 mg/kg) and sacrificed 24 h later. The tibialis anterior (TA),
soleus (SOLD) and diaphragm (DIA) muscles were quickly excised and
examined for mitochondrial morphological injury, Ca++ retention capacity
and biogenesis. Autophagy was detected with electron microscopy,
lipidation of Lc3b proteins and by measuring gene expression of several
autophagy-related genes. Electron microscopy revealed ultrastructural
injuries in the mitochondria of each muscle, however, injuries were more
severe in the TA and SOL muscles than they were in the DIA. Gene
expressions of nuclear and mitochondrial DNA transcription factors and
co-activators (indicators of biogenesis) were significantly depressed in
all treated muscles, although to a greater extent in the TA and SOL
muscles. Significant autophagosome formation, Lc3b protein lipidation
and upregulation of autophagy-related proteins were detected to a
greater extent in the TA and SOL muscles and less so in the DIA.
Lipidation of Lc3b and the degree of induction of autophagy-related
proteins were significantly blunted in mice expressing a muscle-specific
I kappa B alpha superrepresor.
Conclusion/Significance: We conclude that locomotor muscles are more
prone to sepsis-induced mitochondrial injury, decreased biogenesis and
increased autophagy compared with the ventilatory muscles and that
autophagy in skeletal muscles during sepsis is regulated in part through
the NF kappa B transcription factor