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Relevance of Mitochondrial Dysfunction in the Reserpine-Induced Experimental Fibromyalgia Model

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Abstract

Fibromyalgia (FM) is one of the most common musculoskeletal pain conditions. Although the aetiology of FM is still unknown, mitochondrial dysfunction and the overproduction of reactive oxygen intermediates (ROI) are common characteristics in its pathogenesis. The reserpine experimental model can induce FM-related symptoms in rodents by depleting biogenic amines. However, it is unclear whether reserpine causes other pathophysiologic characteristics of FM. So far, no one has investigated the relevance of mitochondrial dysfunction in the reserpine-induced experimental FM model using protection- and insult-based mitochondrial modulators. Reserpine (1 mg/kg) was subcutaneously injected once daily for three consecutive days in male Swiss mice. We carried out analyses of reserpine-induced FM-related symptoms, and their modulation by using mitochondrial insult on ATP synthesis (oligomycin; 1 mg/kg, intraperitoneally) or mitochondrial protection (coenzyme Q10; 150 mg/kg/5 days, orally). We also evaluated the effect of reserpine on mitochondrial function using high-resolution respirometry and oxidative status. Reserpine caused nociception, loss in muscle strength, and anxiety- and depressive-like behaviours in mice that were consistent with clinical symptoms of FM, without inducing body weight and temperature alterations or motor impairment. Reserpine-induced FM-related symptoms were increased by oligomycin and reduced by coenzyme Q10 treatment. Reserpine caused mitochondrial dysfunction by negatively modulating the electron transport system and mitochondrial respiration (ATP synthesis) mainly in oxidative muscles and the spinal cord. These results support the role of mitochondria in mediating oxidative stress and FM symptoms in this model. In this way, reserpine-inducing mitochondrial dysfunction and increased production of ROI contribute to the development and maintenance of nociceptive, fatigue, and depressive-like behaviours.

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Abbreviations

FM:

Fibromyalgia

ROI:

Reactive oxygen intermediates

CoQ10:

Coenzyme Q10

H2O2 :

Hydrogen peroxide

PWT:

Paw withdrawal threshold

B1:

Baseline 1

B2:

Baseline 2

BIOPS:

Biopsy preservation solution

MIR05:

Mitochondrial respiration medium 05

HRR:

High-resolution respirometry

SUIT:

Titration of multiple substrates, uncouplers, and inhibitors

CI:

Complex I

CII:

Complex II

OXPHOS:

Oxidative phosphorylation

PMG:

Pyruvate, malate, and glutamate

ETS:

Electron transport system

CS:

Citrate synthase

LDH:

Lactate dehydrogenase

DCF:

Dichlorofluorescein

DCFDA:

Dichlorofluorescein diacetate

HRPO:

Horseradish peroxidase

CAT:

Catalase

TBARS:

Thiobarbituric acid reactive species

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Funding

This study was supported by the Fundação de Amparo à Pesquisa do Estado do Rio Grande do Sul-FAPERGS and by the Conselho Nacional de Desenvolvimento Científico e Tecnológico-CNPq (Grant #16/2551-0000281-9); by FAPERGS (Grant #17/2551-0001082-5) (Brazil); by the CNPq (process #406098/2018-2); by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior - CAPES/PROEX (process 23038.004173/2019-93, grant #0493/2019); and by PRONEM/FAPERGS/CNPQ (#16/2551-0000248-7). S.M.O is recipient of fellowship from CNPq (process #307220/2017-6) and E.S.B, M.F.P.F., D.F.G., and D.D.H. are recipients of fellowship from CAPES/PROEX (process #88887.185973/2018-00, #88882.182170/2018-01, #88882.182139/2018-01, and #88882.182131/2018-01, respectively). S.P.M.F. is recipient of fellowship from CNPq (process #134613/2017-1). We thank CNPq and CAPES for their fellowship support.

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Authors and Affiliations

  1. Graduate Program in Biological Sciences, Biochemical Toxicology, Center of Natural and Exact Sciences, Federal University of Santa Maria, Camobi, Santa Maria, RS, 97105-900, Brazil

    Evelyne da Silva Brum, Maria Fernanda Pessano Fialho, Susana Paula Moreira Fischer, Diane Duarte Hartmann, Débora Farina Gonçalves, Cristiane Lenz Dalla Corte, Félix Alexandre Antunes Soares & Sara Marchesan Oliveira

  2. Graduate Program in Health Sciences, University of Extreme South Catarinense, Criciúma, SC, Brazil

    Rahisa Scussel & Ricardo Andrez Machado-de-Ávila

  3. Department of Biochemistry and Molecular Biology, Center of Natural and Exact Sciences, Federal University of Santa Maria, Santa Maria, RS, Brazil

    Cristiane Lenz Dalla Corte, Félix Alexandre Antunes Soares & Sara Marchesan Oliveira

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  1. Evelyne da Silva Brum
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  2. Maria Fernanda Pessano Fialho
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Contributions

Study concept and design: ESB and SMO. Acquisition of mitochondrial function data: ESB, DDH, and DFG. Acquisition of behaviours data: ESB, MFPF, and SPMF. Acquisition of biogenic amines data: ESB and RS. Analysis and interpretation of data: ESB, DDH, DFG, and SMO. Drafting and revising the content of the manuscript: ESB, RMA, CLDC, FAAS, and SMO. Study supervision: SMO.

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Correspondence to Sara Marchesan Oliveira.

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All applicable international, national, and institutional guidelines for the care and use of animals were followed. Experiments in animals were performed with the approval of the Institutional Committee for Animal Care and Use of the Federal University of Santa Maria (process numbers 3525100119/2019 and 5070100119/2019).

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Headings

• Oligomycin (ATP insult) enhanced reserpine-induced pain and depressive-like behaviours.

• Coenzyme Q10 prevented reserpine-induced pain and depressive-like behaviours.

• Reserpine reduced electron transport and mitochondrial respiration in the muscles and spinal cord.

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Brum, E.d., Fialho, M.F.P., Fischer, S.P.M. et al. Relevance of Mitochondrial Dysfunction in the Reserpine-Induced Experimental Fibromyalgia Model. Mol Neurobiol 57, 4202–4217 (2020). https://doi.org/10.1007/s12035-020-01996-1

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