Journal article
Disruption of KATP channel expression in skeletal muscle by targeted oligonucleotide delivery promotes activity-linked thermogenesis
Molecular therapy, Vol.23(4), pp.707-716
04/2015
DOI: 10.1038/mt.2015.21
PMCID: PMC4395784
PMID: 25648265
Abstract
Despite the medical, social, and economic impact of obesity, only a few therapeutic options, focused largely on reducing caloric intake, are currently available and these have limited success rates. A major impediment is that any challenge by caloric restriction is counterbalanced by activation of systems that conserve energy to prevent body weight loss. Therefore, targeting energy-conserving mechanisms to promote energy expenditure is an attractive strategy for obesity treatment. Here, in order to suppress muscle energy efficiency, we target sarcolemmal ATP-sensitive potassium (KATP) channels which have previously been shown to be important in maintaining muscle energy economy. Specifically, we employ intramuscular injections of cell-penetrating vivo-morpholinos to prevent translation of the channel pore-forming subunit. This intervention results in significant reduction of KATP channel expression and function in treated areas, without affecting the channel expression in nontargeted tissues. Furthermore, suppression of KATP channel function in a group of hind limb muscles causes a substantial increase in activity-related energy consumption, with little effect on exercise tolerance. These findings establish a proof-of-principle that selective skeletal muscle targeting of sarcolemmal KATP channel function is possible and that this intervention can alter overall bodily energetics without a disabling impact on muscle mechanical function.
Details
- Title: Subtitle
- Disruption of KATP channel expression in skeletal muscle by targeted oligonucleotide delivery promotes activity-linked thermogenesis
- Creators
- Siva Rama Krishna Koganti - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAZhiyong Zhu - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAEkaterina Subbotina - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAZhan Gao - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAAna Sierra - Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USAManuel Proenza - Department of Pediatrics, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USALiping Yang - Veterans Affairs Medical Center, Iowa City, Iowa, USAAlexey Alekseev - Department of Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USADenice Hodgson-Zingman - 1] Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA François Abboud Cardiovascular Research Center, University of Iowa, Iowa City, Iowa, USALeonid Zingman - 1] Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, USA Veterans Affairs Medical Center, Iowa City, Iowa, USA Fraternal Order of Eagles Diabetes Research Center, University of Iowa, Iowa City, Iowa, USA François Abboud Cardiovascular Research Center, University of Iowa, Iowa City, Iowa, USA
- Resource Type
- Journal article
- Publication Details
- Molecular therapy, Vol.23(4), pp.707-716
- DOI
- 10.1038/mt.2015.21
- PMID
- 25648265
- PMCID
- PMC4395784
- ISSN
- 1525-0016
- eISSN
- 1525-0024
- Grant note
- I01 BX000718 / BLRD VA R01 DK092412 / NIDDK NIH HHS HL113089 / NHLBI NIH HHS R01 HL113089 / NHLBI NIH HHS DK092412 / NIDDK NIH HHS
- Language
- English
- Date published
- 04/2015
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Cardiovascular Medicine; Internal Medicine
- Record Identifier
- 9984094334702771
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