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Kinin-B2 Receptor Activity in Skeletal Muscle Regeneration and Myoblast Differentiation

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Abstract

The bioactive peptide bradykinin obtained from cleavage of precursor kininogens activates the kinin-B2 receptor functioning in induction of inflammation and vasodilatation. In addition, bradykinin participates in kidney and cardiovascular development and neuronal and muscle differentiation. Here we show that kinin-B2 receptors are expressed throughout differentiation of murine C2C12 myoblasts into myotubes. An autocrine loop between receptor activation and bradykinin secretion is suggested, since bradykinin secretion is significantly reduced in the presence of the kinin-B2 receptor antagonist HOE-140 during differentiation. Expression of skeletal muscle markers and regenerative capacity were decreased after pharmacological inhibition or genetic ablation of the B2 receptor, while its antagonism increased the number of myoblasts in culture. In summary, the present work reveals to date no functions described for the B2 receptor in muscle regeneration due to the control of proliferation and differentiation of muscle precursor cells.

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Fig. 1: Muscle regeneration following cardiotoxin injection into WT and B2BKR −/− rectus femoral skeletal muscles.
Fig. 2: Kininogen mRNA transcription and bradykinin secretion into the culture medium during muscle differentiation of C2C12 cells.
Fig. 3: Myoblast differentiation depends on B2BKR activity in vitro and in vivo.
Fig. 4: Analysis of myoblasts, nascent and mature myotubes in C2C12 culture under condition of differentiation and B2BKR inhibition.

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Funding

This work was supported by grants awarded by Fundação de Amparo à Pesquisa do Estado de São Paulo (São Paulo Research Foundation, FAPESP, Project No. 2012/50880-4) and CNPq (Conselho Nacional de Desenvolvimento Científico e Tecnológico), Brazil, to H.U. and C.L. (2015/19128-2), by a NIH grant, to A.H.M (8G12MD007600) and by the Universidad Central del Caribe Biomedical Proteomics Facility Grant G12MD007583 awarded to NMB from the NIH National Institute on Minority Health and Health Disparities (NIMHD) RCMI Program.. J.M.A.’s Ph.D. thesis research was funded by CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), Brazil. This study was financed by Coordenação de Aperfeiçoamento de Pessoal de Nível Superior -Brazil (CAPES) – Finance Code 001.

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Author notes

  1. Janaina M. Alves

    Present address: Department of Microbiology and Immunology, Universidad Central del Caribe, Bayamón, PR, USA

  2. Janaina M. Alves, Antonio H. Martins, Claudiana Lameu and Talita Glaser contributed equally to this work.

Authors and Affiliations

  1. Departmento de Neurologia/Neurocirurgia, Universidade Federal de São Paulo, São Paulo, 04023-900, Brazil

    Janaina M. Alves & Isis C. Nascimento

  2. Pharmacology and Toxicology Department, University of Puerto Rico Medical -Sciences Campus, Rio Piedras, PR, USA

    Antonio H. Martins

  3. Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Av. Prof. Lineu Prestes 748, São Paulo, S.P., 05508-000, Brazil

    Antonio H. Martins, Claudiana Lameu, Talita Glaser, Isis C. Nascimento, Poliana C. M. Martins, Héllio D. N. de Souza & Henning Ulrich

  4. Biomedical Proteomics Facility, Department of Microbiology and Immunology, Universidad Central del Caribe, Bayamón, PR, USA

    Nawal M. Boukli

  5. Heart Institute (InCor), University of São Paulo Medical School, São Paulo, Brazil

    Vinicius Bassaneze, Rafael Dariolli, José Eduardo Krieger & Dulce E. Casarini

  6. Departamento de Biofísica, Universidade Federal de São Paulo, São Paulo, 04023-900, Brazil

    Vicencia M. Sales & João B. Pesquero

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  1. Janaina M. Alves
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Correspondence to Henning Ulrich.

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Summary statement

A novel function of bradykinin is described for muscle differentiation and repair.

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Alves, J.M., Martins, A.H., Lameu, C. et al. Kinin-B2 Receptor Activity in Skeletal Muscle Regeneration and Myoblast Differentiation. Stem Cell Rev and Rep 15, 48–58 (2019). https://doi.org/10.1007/s12015-018-9850-9

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