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Skeletal muscle derived Musclin protects the heart during pathological overload.

ABSTRACT: Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. Here, we investigate whether the dysregulation of myokine expression from wasting skeletal muscle exaggerates heart failure. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression of Ostn, which encodes the secreted myokine Musclin, previously implicated in the enhancement of natriuretic peptide signaling. By generating skeletal muscle specific Ostn knock-out and overexpressing mice, we demonstrate that reduced skeletal muscle Musclin levels exaggerate, while its overexpression in muscle attenuates cardiac dysfunction and myocardial fibrosis during pressure overload. Mechanistically, Musclin enhances the abundance of C-type natriuretic peptide (CNP), thereby promoting cardiomyocyte contractility through protein kinase A and inhibiting fibroblast activation through protein kinase G signaling. Because we also find reduced OSTN expression in skeletal muscle of heart failure patients, augmentation of Musclin might serve as therapeutic strategy.

SUBMITTER: Szaroszyk M

PROVIDER: S-EPMC8748430 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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Skeletal muscle derived Musclin protects the heart during pathological overload.

Szaroszyk Malgorzata M Kattih Badder B Martin-Garrido Abel A Trogisch Felix A FA Dittrich Gesine M GM Grund Andrea A Abouissa Aya A Derlin Katja K Meier Martin M Holler Tim T Korf-Klingebiel Mortimer M Völker Katharina K Garfias Macedo Tania T Pablo Tortola Cristina C Boschmann Michael M Huang Nora N Froese Natali N Zwadlo Carolin C Malek Mohammadi Mona M Luo Xiaojing X Wagner Michael M Cordero Julio J Geffers Robert R Batkai Sandor S Thum Thomas T Bork Nadja N Nikolaev Viacheslav O VO Müller Oliver J OJ Katus Hugo A HA El-Armouche Ali A Kraft Theresia T Springer Jochen J Dobreva Gergana G Wollert Kai C KC Fielitz Jens J von Haehling Stephan S Kuhn Michaela M Bauersachs Johann J Heineke Joerg J

Nature communications 20220110 1

Cachexia is associated with poor prognosis in chronic heart failure patients, but the underlying mechanisms of cachexia triggered disease progression remain poorly understood. Here, we investigate whether the dysregulation of myokine expression from wasting skeletal muscle exaggerates heart failure. RNA sequencing from wasting skeletal muscles of mice with heart failure reveals a reduced expression of Ostn, which encodes the secreted myokine Musclin, previously implicated in the enhancement of n ...[more]

PMID: 35013221

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Project description:The role of long noncoding RNA (lncRNA) in adult hearts is unknown; also unclear is how lncRNA modulates nucleosome remodelling. An estimated 70% of mouse genes undergo antisense transcription1, including myosin heavy chain 7 (Myh7), which encodes molecular motor proteins for heart contraction2. Here we identify a cluster of lncRNA transcripts from Myh7 loci and demonstrate a new lncRNA–chromatin mechanism for heart failure. In mice, these transcripts, which we named myosin heavy-chain-associated RNA transcripts (Mhrt), are cardiac-specific and abundant in adult hearts. Pathological stress activates the Brg1–Hdac–Parp chromatin repressor complex3 to inhibit Mhrt transcription in the heart. Such stress-induced Mhrt repression is essential for cardiomyopathy to develop: restoring Mhrt to the pre-stress level protects the heart from hypertrophy and failure. Mhrt antagonizes the function of Brg1, a chromatin-remodelling factor that is activated by stress to trigger aberrant gene expression and cardiac myopathy3. Mhrt prevents Brg1 from recognizing its genomic DNA targets, thus inhibiting chromatin targeting and gene regulation by Brg1. It does so by binding to the helicase domain of Brg1, a domain that is crucial for tethering Brg1 to chromatinized DNA targets. Brg1 helicase has dual nucleic-acid-binding specificities: it is capable of binding lncRNA (Mhrt) and chromatinized—but not naked—DNA. This dual-binding feature of helicase enables a competitive inhibition mechanism by which Mhrt sequesters Brg1 from its genomic DNA targets to prevent chromatin remodelling. A Mhrt–Brg1 feedback circuit is thus crucial for heart function. Human MHRT also originates from MYH7 loci and is repressed in various types of myopathic hearts, suggesting a conserved lncRNA mechanism in human cardiomyopathy. Our studies identify a cardioprotective lncRNA, define a new targeting mechanism for ATP-dependent chromatin-remodelling factors, and establish a new paradigm for lncRNA–chromatin interaction. Overexpression of murine non-coding RNAs in human cell line, comparison of RNA-sequencing with Ribosome Profiling

Dataset Information

Skeletal muscle derived Musclin protects the heart during pathological overload.

Publications

Skeletal muscle derived Musclin protects the heart during pathological overload.

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