Functional significance of gain-of-function H19 lncRNA in skeletal muscle differentiation and anti-obesity effects

Genome Medicine

Preethi H. Gunaratne¹  Sujash S. Chatterjee¹  Brandon Mistretta¹  Yinghong Pan²  Zhao Zhang³  Youqiong Ye³  Leng Han⁴  Tina K. Nguyen⁵  Qingsong Hu⁵  Yajuan Li⁵  Ke Liang⁵  Yaohua Zhang⁵  Sergey D. Egranov⁵  Chunru Lin⁶  Liuqing Yang⁷  Zhen Xing⁸  David H. Hawke⁹  Mien-Chie Hung^1,10 

[1] Department of Biochemistry and Biology, University of Houston, 77204, Houston, TX, USA;Department of Biochemistry and Biology, University of Houston, 77204, Houston, TX, USA;Current address: UPMC Genome Center, 15232, Pittsburgh, PA, USA;Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, 77030, Houston, TX, USA;Department of Biochemistry and Molecular Biology, The University of Texas Health Science Center at Houston McGovern Medical School, 77030, Houston, TX, USA;Center for Epigenetics and Disease Prevention, Institute of Biosciences and Technology, Texas A&M University, 77030, Houston, TX, USA;Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;The Graduate School of Biomedical Sciences, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;Current address: Sanofi U.S., 02139, Boston, MA, USA;Department of Systems Biology, The University of Texas MD Anderson Cancer Center, 77030, Houston, TX, USA;Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, 404, Taichung, Taiwan;Department of Biotechnology, Asia University, 413, Taichung, Taiwan;

关键词: Long noncoding RNA;    H19;    Skeletal muscle;    Obesity;    RNA therapy;    Dystrophin;   

DOI  :  10.1186/s13073-021-00937-4

来源: Springer

【 摘 要 】

BackgroundExercise training is well established as the most effective way to enhance muscle performance and muscle building. The composition of skeletal muscle fiber type affects systemic energy expenditures, and perturbations in metabolic homeostasis contribute to the onset of obesity and other metabolic dysfunctions. Long noncoding RNAs (lncRNAs) have been demonstrated to play critical roles in diverse cellular processes and diseases, including human cancers; however, the functional importance of lncRNAs in muscle performance, energy balance, and obesity remains elusive. We previously reported that the lncRNA H19 regulates the poly-ubiquitination and protein stability of dystrophin (DMD) in muscular dystrophy.MethodsHere, we identified mouse/human H19-interacting proteins using mouse/human skeletal muscle tissues and liquid chromatography–mass spectrometry (LC-MS). Human induced pluripotent stem-derived skeletal muscle cells (iPSC-SkMC) from a healthy donor and Becker Muscular Dystrophy (BMD) patients were utilized to study DMD post-translational modifications and associated proteins. We identified a gain-of-function (GOF) mutant of H19 and characterized the effects on myoblast differentiation and fusion to myotubes using iPSCs. We then conjugated H19 RNA gain-of-function oligonucleotides (Rgof) with the skeletal muscle enrichment peptide agrin (referred to as AGR-H19-Rgof) and evaluated AGR-H19-Rgof’s effects on skeletal muscle performance using wild-type (WT) C57BL/6 J mice and its anti-obesity effects using high-fat diet (HFD)- and leptin deficiency-induced obese mouse models.ResultsWe demonstrated that both human and mouse H19 associated with DMD and that the H19 GOF exhibited enhanced interaction with DMD compared to WT H19. DMD was found to associate with serine/threonine-protein kinase MRCK alpha (MRCKα) and α-synuclein (SNCA) in iPSC-SkMC derived from BMD patients. Inhibition of MRCKα and SNCA-mediated phosphorylation of DMD antagonized the interaction between H19 and DMD. These signaling events led to improved skeletal muscle cell differentiation and myotube fusion. The administration of AGR-H19-Rgof improved the muscle mass, muscle performance, and base metabolic rate of WT mice. Furthermore, mice treated with AGR-H19-Rgof exhibited resistance to HFD- or leptin deficiency-induced obesity.ConclusionsOur study suggested the functional importance of the H19 GOF mutant in enhancing muscle performance and anti-obesity effects.

【 授权许可】

CC BY