title: Metformin and caloric restriction induce an AMPK-dependent restoration of mitochondrial dysfunction in fibroblasts from Fibromyalgia patients.
abstract: Impaired AMPK is associated with a wide spectrum of clinical and pathological conditions, ranging from obesity, altered responses to exercise or metabolic syndrome, to inflammation, disturbed mitochondrial biogenesis and defective response to energy stress. Fibromyalgia (FM) is a world-wide diffused musculoskeletal chronic pain condition that affects up to 5% of the general population and comprises all the above mentioned pathophysiological states. Here, we tested the involvement of AMPK activation in fibroblasts derived from FM patients. AMPK was not phosphorylated in fibroblasts from FM patients and was associated with decreased mitochondrial biogenesis, reduced oxygen consumption, decreased antioxidant enzymes expression levels and mitochondrial dysfunction. However, mtDNA sequencing analysis did not show any important alterations which could justify the mitochondrial defects. AMPK activation in FM fibroblast was impaired in response to moderate oxidative stress. In contrast, AMPK activation by metformin or incubation with serum from caloric restricted mice improved the response to moderate oxidative stress and mitochondrial metabolism in FM fibroblasts. These results suggest that AMPK plays an essential role in FM pathophysiology and could represent the basis for a valuable new therapeutic target/strategy. Furthermore, both metformin and caloric restriction could be an interesting therapeutic approach in FM.
authors.affiliation: Research Laboratory, Oral Medicine Department, Universidad de Sevilla, Sevilla, Spain; Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide-CSIC-Junta de Andalucía and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 41013 Sevilla, Spain.
authors.forename: Elísabet
authors.initials: E
authors.lastname: Alcocer-Gómez
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide-CSIC-Junta de Andalucía and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 41013 Sevilla, Spain.
authors.forename: Juan
authors.initials: J
authors.lastname: Garrido-Maraver
authors.affiliation: Research Laboratory, Oral Medicine Department, Universidad de Sevilla, Sevilla, Spain; Dept. of Periodontology, Dental School, University of Sevilla, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Bullón
authors.affiliation: Research Laboratory, Oral Medicine Department, Universidad de Sevilla, Sevilla, Spain.
authors.forename: Fabiola
authors.initials: F
authors.lastname: Marín-Aguilar
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide-CSIC-Junta de Andalucía and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 41013 Sevilla, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Cotán
authors.affiliation: División de Neurociencias, Universidad Pablo de Olavide de Sevilla, Carretera de Utrera Km. 1, 41013 Sevilla, Spain.
authors.forename: Angel M
authors.initials: AM
authors.lastname: Carrión
authors.affiliation: Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche (DISCO)-Sez. Biochimica, Facoltà di Medicina, Università Politecnica delle Marche, Ancona 60131, Italy; Area de Nutrición y Salud, Universidad Internacional Iberoamericana (UNINI), Campeche C.P.24040, Mexico; Facultad de Ciencias de la Salud, Universidad Nacional de Chimborazo, Riobamba, Ecuador.
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Alvarez-Suarez
authors.affiliation: Dipartimento di Scienze Agrarie, Alimentari e Ambientali (D3A), Università Politecnica delle Marche, Via Ranieri 65, Ancona 60131, Italy.
authors.forename: Francesca
authors.initials: F
authors.lastname: Giampieri
authors.affiliation: Centro Andaluz de Biología del Desarrollo (CABD), Universidad Pablo de Olavide-CSIC-Junta de Andalucía and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), ISCIII, 41013 Sevilla, Spain.
authors.forename: José Antonio
authors.initials: JA
authors.lastname: Sánchez-Alcazar
authors.affiliation: Dipartimento di Scienze Cliniche Specialistiche ed Odontostomatologiche (DISCO)-Sez. Biochimica, Facoltà di Medicina, Università Politecnica delle Marche, Ancona 60131, Italy; Director Centre for Nutrition & Health, Universidad Europea del Atlantico (UEA), Santander 39011, Spain.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Battino
authors.affiliation: Research Laboratory, Oral Medicine Department, Universidad de Sevilla, Sevilla, Spain. Electronic address: mdcormor@us.es.
authors.forename: Mario D
authors.initials: MD
authors.lastname: Cordero
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000328:Adult; D000818:Animals; D031204:Caloric Restriction; D016022:Case-Control Studies; D002478:Cells, Cultured; D004272:DNA, Mitochondrial / Q000235:genetics; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism*; D005356:Fibromyalgia / Q000378:metabolism*; D006801:Humans; D008297:Male; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D018384:Oxidative Stress
chemical_list: D004272:DNA, Mitochondrial; D008687:Metformin; D055372:AMP-Activated Protein Kinases
keywords: AMPK; Caloric restriction; Fibromyalgia; Metformin; Mitochondria; Oxidative stress