The MicroRNA miR-696 is regulated by SNARK and reduces mitochondrial activity in mouse skeletal muscle through Pgc1α inhibition

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dc.creatorAndré L. Queiroz
dc.creatorMichael F. Hirshman
dc.creatorLuciane C. Alberici
dc.creatorIsis do Carmo Kettelhut
dc.creatorLaurie J. Goodyear
dc.creatorLeonardo R. Silveira
dc.creatorSarah J. Lessard
dc.creatorAmanda T. Ouchida
dc.creatorHygor N. Araujo
dc.creatorDawit Albieiro Pinheiro Gonçalves
dc.creatorDimitrius Santiago P. Simões Fróes Guimarães
dc.creatorBruno G. Teodoro
dc.creatorKawai So
dc.creatorEnilza M. Espreafico
dc.date.accessioned2024-02-27T16:24:29Z
dc.date.accessioned2025-09-08T23:37:56Z
dc.date.available2024-02-27T16:24:29Z
dc.date.issued2021
dc.description.sponsorshipCAPES - Coordenação de Aperfeiçoamento de Pessoal de Nível Superior
dc.description.sponsorshipFAPESP - Fundação de Amparo à Pesquisa do Estado de São Paulo
dc.format.mimetypepdf
dc.identifier.doihttps://doi.org/10.1016/j.molmet.2021.101226
dc.identifier.issn2212-8778
dc.identifier.urihttps://hdl.handle.net/1843/64806
dc.languageeng
dc.publisherUniversidade Federal de Minas Gerais
dc.relation.ispartofMolecular Metabolism
dc.rightsAcesso Aberto
dc.subjectFisiologia
dc.subjectMorfologia vegetal
dc.subjectMúsculos
dc.subjectMitocôndrias
dc.subject.otherMiR-696
dc.subject.otherMitochondrial function
dc.subject.otherSkeletal muscle
dc.subject.otherSNARK
dc.subject.otherPgc1a
dc.titleThe MicroRNA miR-696 is regulated by SNARK and reduces mitochondrial activity in mouse skeletal muscle through Pgc1α inhibition
dc.typeArtigo de periódico
local.citation.epage14
local.citation.spage101226
local.citation.volume51
local.description.resumoObjective MicroRNAs (miRNA) are known to regulate the expression of genes involved in several physiological processes including metabolism, mitochondrial biogenesis, proliferation, differentiation, and cell death. Methods Using “in silico” analyses, we identified 219 unique miRNAs that potentially bind to the 3′UTR region of a critical mitochondrial regulator, the peroxisome proliferator-activated receptor gamma coactivator (PGC) 1 alpha (Pgc1α). Of the 219 candidate miRNAs, miR-696 had one of the highest interactions at the 3′UTR of Pgc1α, suggesting that miR-696 may be involved in the regulation of Pgc1α. Results Consistent with this hypothesis, we found that miR-696 was highly expressed in the skeletal muscle of STZ-induced diabetic mice and chronic high-fat-fed mice. C2C12 muscle cells exposed to palmitic acid also exhibited a higher expression of miR-696. This increased expression corresponded with a reduced expression of oxidative metabolism genes and reduced mitochondrial respiration. Importantly, reducing miR-696 reversed decreases in mitochondrial activity in response to palmitic acid. Using C2C12 cells treated with the AMP-activated protein kinase (AMPK) activator AICAR and skeletal muscle from AMPKα2 dominant-negative (DN) mice, we found that the signaling mechanism regulating miR-696 did not involve AMPK. In contrast, overexpression of SNF1-AMPK-related kinase (SNARK) in C2C12 cells increased miR-696 transcription while knockdown of SNARK significantly decreased miR-696. Moreover, muscle-specific transgenic mice overexpressing SNARK exhibited a lower expression of Pgc1α, elevated levels of miR-696, and reduced amounts of spontaneous activity. Conclusions Our findings demonstrate that metabolic stress increases miR-696 expression in skeletal muscle cells, which in turn inhibits Pgc1α, reducing mitochondrial function. SNARK plays a role in this process as a metabolic stress signaling molecule inducing the expression of miR-696.
local.identifier.orcidhttps://orcid.org/0000-0003-2621-3330
local.publisher.countryBrasil
local.publisher.departmentEEF - DEPARTAMENTO DE EDUCAÇÃO FÍSICA
local.publisher.departmentEEFFTO - ESCOLA DE EDUCAÇÃO FISICA, FISIOTERAPIA E TERAPIA OCUPACIONAL
local.publisher.initialsUFMG
local.url.externahttps://www.sciencedirect.com/science/article/pii/S2212877821000715?via%3Dihub

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