A Small Volatile Bacterial Molecule Triggers Mitochondrial Dysfunction in Murine Skeletal Muscle

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.

Exercise oxidative skeletal muscle metabolism in adolescents with cystic fibrosis

“…Additionally, in a recent mouse study, acute P. aeruginosa colonization was demonstrated to induce insulin resistance and mitochondrial dysfunction in the skeletal muscles (Tzika et al . ). Additionally, no evidence is available concerning the effect of exercise training on the skeletal muscle metabolism in patients with CF with more severe disease and more systemic inflammation (Van de Weert‐van Leeuwen et al .…”

Applications of high‐resolution magic angle spinning MRS in biomedical studies I—cell line and animal models

“…Lipids are also considered to be useful biomarkers for conditions other than cancer. Studies investigated the viability of intramyocellular lipids (IMCLs) and other molecules as biomarkers in burn trauma and infections caused by Pseudomonas aeruginosa , an opportunistic pathogen commonly found in soil and water, that typically infects the human airway, urinary tract, burns, and wounds . In these studies, IMCLs showed significant increases with severity of the condition and could serve as biomarkers for grading the progression of a Pseudomonas aeruginosa infection as well as for the therapeutic effectiveness in burn trauma patients.…”

Modulation of SIRT1-Foxo1 Signaling axis by Resveratrol: Implications in Skeletal Muscle Aging and Insulin Resistance

“…Reduced contractile function of skeletal muscle has been demonstrated to accompany the down-regulation of SIRT1 and IRS1 [49]. Although further studies are required to dissect the physiological effects of SIRT1-mediated deacetylation of IRS1, phosphorylation of IRS1 at serine-307 is considered as a molecular event that precedes and associates with the development of glucose intolerance [50,51].…”