Lipopolysaccharide Disrupts Mitochondrial Physiology in Skeletal Muscle via Disparate Effects on Sphingolipid Metabolism

Shock. 2015 Dec;44(6):585-92. doi: 10.1097/SHK.0000000000000468.

Abstract

Lipopolysaccharides (LPS) are prevalent pathogenic molecules that are found within tissues and blood. Elevated circulating LPS is a feature of obesity and sepsis, both of which are associated with mitochondrial abnormalities that are key pathological features of LPS excess. However, the mechanism of LPS-induced mitochondrial alterations remains poorly understood. Herein we demonstrate the necessity of sphingolipid accrual in mediating altered mitochondrial physiology in skeletal muscle following LPS exposure. In particular, we found LPS elicited disparate effects on the sphingolipids dihydroceramides (DhCer) and ceramides (Cer) in both cultured myotubes and in muscle of LPS-injected mice. Although LPS-treated myotubes had reduced DhCer and increased Cer as well as increased mitochondrial respiration, muscle from LPS-injected mice manifested a reverse trend, namely elevated DhCer, but reduced Cer as well as reduced mitochondrial respiration. In addition, we found that LPS treatment caused mitochondrial fission, likely via dynamin-related protein 1, and increased oxidative stress. However, inhibition of de novo sphingolipid biosynthesis via myriocin protected normal mitochondrial function in spite of LPS, but inhibition of DhCer desaturase 1, which increases DhCer, but not Cer, exacerbated mitochondrial respiration with LPS. In an attempt to reconcile the incongruent effects of LPS in isolated muscle cells and whole muscle tissue, we incubated myotubes with conditioned medium from treated macrophages. In contrast to direct myotube LPS treatment, conditioned medium from LPS-treated macrophages reduced myotube respiration, but this was again mitigated with sphingolipid inhibition. Thus, macrophage sphingolipid production appears to be necessary for LPS-induced mitochondrial alterations in skeletal muscle tissue.

MeSH terms

  • Animals
  • Cell Respiration
  • Ceramides / chemistry
  • Culture Media, Conditioned / chemistry
  • Lipid Metabolism
  • Lipids / chemistry
  • Lipopolysaccharides / chemistry*
  • Macrophages / cytology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria, Muscle / metabolism*
  • Muscle Fibers, Skeletal / metabolism
  • Muscle, Skeletal / metabolism*
  • Muscle, Skeletal / physiopathology
  • Oxidative Stress
  • Oxygen Consumption
  • Reactive Oxygen Species / metabolism
  • Real-Time Polymerase Chain Reaction
  • Sphingolipids / metabolism*

Substances

  • Ceramides
  • Culture Media, Conditioned
  • Lipids
  • Lipopolysaccharides
  • Reactive Oxygen Species
  • Sphingolipids
  • dihydroceramide