Abstract
Fibromyalgia (FM) is characterized by chronic widespread pain. The pathogenesis of FM remains unclear. No specific biomarkers are available. Animal models of FM may provide an opportunity to explore potential biomarkers in a relative homogenous disease condition. Here, we probed the metabolomics profiles of serum and urine in a mouse model of FM induced by intermittent cold stress (ICS). We focused on the role of acid-sensing ion channel 3 (ASIC3) in the metabolomics profiling because ICS treatment induced chronic widespread muscle pain lasting for 1 month in wild-type (Asic3+/+) but not Asic3-knockout (Asic3−/−) mice. Serum and urine samples were collected from both genotypes at different ICS stages, including before ICS (basal level) and post-ICS at days 10 (middle phase, P10) and 40 (recovery phase, P40). Control naïve mice and ICS-induced FM mice differed in 1H-NMR- and LC-MS-based metabolomics profiling. On pathway analysis, the leading regulated pathways in Asic3+/+ mice were taurine and hypotaurine, cysteine and methionine, glycerophospholipid, and ascorbate and aldarate metabolisms, and the major pathways in Asic3−/− mice involved amino acid-related metabolism. Finally, we developed an algorithm for the impactful metabolites in the FM model including cis-aconitate, kynurenate, taurine, pyroglutamic acid, pyrrolidonecarboxylic acid, and 4-methoxyphenylacetic acid in urine as well as carnitine, deoxycholic acid, lysoPC(16:0), lysoPC(20:3), oleoyl-L-carnitine, and trimethylamine N-oxide in serum. Asic3−/− mice were impaired in only muscle allodynia development but not other pain symptoms in the ICS model, so the ASIC3-dependent metabolomics changes could be useful for developing diagnostic biomarkers specific to chronic widespread muscle pain, the core symptom of FM. Further pharmacological validations are needed to validate these metabolomics changes as potential biomarkers for FM diagnosis and/or treatment responses.
Highlights
Fibromyalgia (FM) is characterized by chronic widespread musculoskeletal pain affecting 2% to 8% of the adult population, with high prevalence in women[1]
Acid-sensing ion channel 3 (ASIC3) is involved in the development of chronic widespread muscle pain in an FM model induced by repeated intramuscular acid injection, its role in other FM models is unknown
These results suggest a role for ASIC3 in the stress-induced chronic widespread muscle pain
Summary
Fibromyalgia (FM) is characterized by chronic widespread musculoskeletal pain affecting 2% to 8% of the adult population, with high prevalence in women[1]. Intermittent cold stress (ICS) is one of well-established mouse model of FM, in which widespread and long-lasting muscle allodynia is induced after a sudden and frequent change of environment temperature. ICS is an ideal animal model of FM to investigate the underlying mechanisms of chronic widespread pain as well as possible diagnostic biomarkers and a therapeutic strategy. Previous studies of rodent models induced by repeated intramuscular acid injection have shown that ASIC3 is involved in FM-like pain[14,15,16]. Lacking ASIC3 signaling would impair chronic muscle pain development in the ICS model and change the metabolomics profiling in serum and urine. We profiled the metabolomics of the Asic[3] wild-type and -knockout mouse models at different stages of ICS treatment to identify ASIC3-dependent metabolic changes. We aimed to probe meaningful metabolic biomarkers that could be used for diagnosis of FM
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