Abstract
BackgroundMitochondrial 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 FindingsAdult 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 IκBα superrepresor.Conclusion/SignificanceWe 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 NFκB transcription factor.
Highlights
Severe sepsis elicits mitochondrial injury, dysfunction and depressed biogenesis in skeletal muscles
LPS administration increased the proportion of mitochondria with morphological abnormalities in all muscles, the degree of mitochondrial ultrastructure damage was greater in tibialis anterior (TA) muscles (.20% of mitochondria had a score of 0) and SOL, as compared to the DIA (,5% of mitochondria had a score of 0) (Figure 2)
The main findings of this study are: 1) LPS administration in mice elicits extensive mitochondrial morphological abnormalities in skeletal muscles that coincide with increased susceptibility to permeability transition pore (PTP) opening and decreased mitochondrial biogenesis; 2) These changes in the muscle mitochondria were associated with significant induction of autophagy in skeletal muscles; 3) LPSinduced mitochondrial injury, inhibition of mitochondrial biogenesis, autophagosome formation and increased expressions of autophagy-related genes are more pronounced in the TA and SOL muscles as compared to the DIA
Summary
Severe sepsis elicits mitochondrial injury, dysfunction and depressed biogenesis in skeletal muscles. During the initial phase of sepsis, these changes are manifested as rapid increases in mitochondrial ATP production [1]. The initial phase of sepsis is usually followed by a second phase, where numbers of mitochondria and activities of various mitochondrial enzymes in skeletal muscles are significantly reduced, rendering cellular ATP production more dependent on glycolysis [4,5,6,7,8]. The second phase has been described by Singer [1] as a pro-survival state of cellular hibernation, wherein protein recycling programs, such as the autophagy-lysosomal degradation pathway, must be activated to provide alternate energy supplies. This study tests the hypotheses that the locomotor muscles are more prone to sepsisinduced mitochondrial injury, depressed biogenesis and autophagy induction compared with the ventilatory muscles
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