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Knockdown of sarcolipin (SLN) impairs substrate utilization in human skeletal muscle cells.
Mengeste, Abel M; Katare, Parmeshwar; Dalmao Fernandez, Andrea; Lund, Jenny; Bakke, Hege G; Baker, David; Bartesaghi, Stefano; Peng, Xiao-Rong; Rustan, Arild C; Thoresen, G Hege; Kase, Eili Tranheim.
Afiliación
  • Mengeste AM; Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068 Blindern, 0316, Oslo, Norway. a.m.mengeste@farmasi.uio.no.
  • Katare P; Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068 Blindern, 0316, Oslo, Norway.
  • Dalmao Fernandez A; Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068 Blindern, 0316, Oslo, Norway.
  • Lund J; Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068 Blindern, 0316, Oslo, Norway.
  • Bakke HG; Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068 Blindern, 0316, Oslo, Norway.
  • Baker D; Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Bartesaghi S; Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Peng XR; Bioscience Metabolism, Research and Early Development Cardiovascular, Renal and Metabolism, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
  • Rustan AC; Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068 Blindern, 0316, Oslo, Norway.
  • Thoresen GH; Section for Pharmacology and Pharmaceutical Biosciences, Department of Pharmacy, University of Oslo, P.O. Box 1068 Blindern, 0316, Oslo, Norway.
  • Kase ET; Department of Pharmacology, Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Mol Biol Rep ; 49(7): 6005-6017, 2022 Jul.
Article en En | MEDLINE | ID: mdl-35364719
BACKGROUND: Recent studies have highlighted that uncoupling of sarco-/endoplasmic reticulum Ca2+-ATPase (SERCA) by sarcolipin (SLN) increases ATP consumption and contributes to heat liberation. Exploiting this thermogenic mechanism in skeletal muscle may provide an attractive strategy to counteract obesity and associated metabolic disorders. In the present study, we have investigated the role of SLN on substrate metabolism in human skeletal muscle cells. METHODS AND RESULTS: After generation of skeletal muscle cells with stable SLN knockdown (SLN-KD), cell viability, glucose and oleic acid (OA) metabolism, mitochondrial function, as well as gene expressions were determined. Depletion of SLN did not influence cell viability. However, glucose and OA oxidation were diminished in SLN-KD cells compared to control myotubes. Basal respiration measured by respirometry was also observed to be reduced in cells with SLN-KD. The metabolic perturbation in SLN-KD cells was reflected by reduced gene expression levels of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and forkhead box O1 (FOXO1). Furthermore, accumulation of OA was increased in cells with SLN-KD compared to control cells. These effects were accompanied by increased lipid formation and incorporation of OA into complex lipids. Additionally, formation of complex lipids and free fatty acid from de novo lipogenesis with acetate as substrate was enhanced in SLN-KD cells. Detection of lipid droplets using Oil red O staining also showed increased lipid accumulation in SLN-KD cells. CONCLUSIONS: Overall, our study sheds light on the importance of SLN in maintaining metabolic homeostasis in human skeletal muscle. Findings from the current study suggest that therapeutic strategies involving SLN-mediated futile cycling of SERCA might have significant implications in the treatment of obesity and associated metabolic disorders.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteolípidos / ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico Límite: Humans Idioma: En Revista: Mol Biol Rep Año: 2022 Tipo del documento: Article País de afiliación: Noruega Pais de publicación: Países Bajos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Proteolípidos / ATPasas Transportadoras de Calcio del Retículo Sarcoplásmico Límite: Humans Idioma: En Revista: Mol Biol Rep Año: 2022 Tipo del documento: Article País de afiliación: Noruega Pais de publicación: Países Bajos