Abstract
Mitochondria integrate distinct signals that reflect specific threats to the host, including infection, tissue damage, and metabolic dysfunction; and play a key role in insulin resistance. We have found that the Pseudomonas aeruginosa quorum sensing infochemical, 2-amino acetophenone (2-AA), produced during acute and chronic infection in human tissues, including in the lungs of cystic fibrosis (CF) patients, acts as an interkingdom immunomodulatory signal that facilitates pathogen persistence, and host tolerance to infection. Transcriptome results have led to the hypothesis that 2-AA causes further harm to the host by triggering mitochondrial dysfunction in skeletal muscle. As normal skeletal muscle function is essential to survival, and is compromised in many chronic illnesses, including infections and CF-associated muscle wasting, we here determine the global effects of 2-AA on skeletal muscle using high-resolution magic-angle-spinning (HRMAS), proton (1H) nuclear magnetic resonance (NMR) metabolomics, in vivo 31P NMR, whole-genome expression analysis and functional studies. Our results show that 2-AA when injected into mice, induced a biological signature of insulin resistance as determined by 1H NMR analysis-, and dramatically altered insulin signaling, glucose transport, and mitochondrial function. Genes including Glut4, IRS1, PPAR-γ, PGC1 and Sirt1 were downregulated, whereas uncoupling protein UCP3 was up-regulated, in accordance with mitochondrial dysfunction. Although 2-AA did not alter high-energy phosphates or pH by in vivo 31P NMR analysis, it significantly reduced the rate of ATP synthesis. This affect was corroborated by results demonstrating down-regulation of the expression of genes involved in energy production and muscle function, and was further validated by muscle function studies. Together, these results further demonstrate that 2-AA, acts as a mediator of interkingdom modulation, and likely effects insulin resistance associated with a molecular signature of mitochondrial dysfunction in skeletal muscle. Reduced energy production and mitochondrial dysfunctional may further favor infection, and be an important step in the establishment of chronic and persistent infections.
Highlights
Pathogens modulate host cell functions to promote their own survival within the host dynamic environment, and to evade the host immune system by hijacking functions of cell organelles, including plasma rafts [1], golgi [2], and mitochondria [3]
Our results demonstrate that 2-amino acetophenone (2-AA) downregulates genes, including peroxisomal proliferator activator receptor (PPAR)-c, PGC-1b and Sirt1 that function in mitochondrial biogenesis, oxidative phosphorylation, and metabolic pathways, including insulin signaling, glucose transport, energy production, fatty acid oxidation, and skeletal muscle function
Our results suggest that PPAR-c suppression could affect energy homeostasis and insulin-induced glucose metabolism in skeletal muscle, which could cause mitochondrial dysfunction and insulin resistance [55], [56]
Summary
Pathogens modulate host cell functions to promote their own survival within the host dynamic environment, and to evade the host immune system by hijacking functions of cell organelles, including plasma rafts [1], golgi [2], and mitochondria [3]. We use Nuclear Magnetic Resonance (NMR) spectroscopy, which can demonstrate mitochondrial dysfunction [35],[36] to assess physiological and metabolic biomarkers in intact muscle; and in vivo NMR, to assess functional mitochondrial metabolism. This technique is superior to biopsy-based genomic analysis, which can only interrogate mitochondrial capacity versus function [37]. Our results show that 2-AA, beyond its previously identified immunomodulatory activity [31], triggers host metabolic changes that occur concurrently with mitochondrial and skeletal muscle dysfunction, to promote pathogenicity
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