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| Status |
Public on Nov 02, 2021 |
| Title |
Skeletal muscle derived Musclin protects the heart during pathological overload |
| Organism |
Mus musculus |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Cachexia is associated with poor prognosis in patients with chronic heart failure. The underlying mechanisms of cachexia triggered heart failure progression, however, are not well understood. Here, we investigated whether the dysregulation of myokine expression from wasting skeletal muscle and impaired inter-organ crosstalk during advanced heart failure might contribute to progression of the disease. RNA sequencing analysis from wasting skeletal muscles of mice with cardiac cachexia during long-term pressure overload revealed a strongly reduced expression of Ostn. Ostn encodes for the skeletal muscle derived myokine Musclin, which had been previously implicated in the enhancement of natriuretic peptide (NP) signaling. Using newly developed skeletal muscle specific, inducible Ostn knock-out mice, we demonstrated that reduced skeletal muscle Musclin levels exaggerated cardiac dysfunction and myocardial fibrosis compared to littermate control mice after TAC. Restoration of Musclin deficiency during cardiac cachexia via AAV6-mediated skeletal muscle specific Musclin overexpression, in turn, attenuated left ventricular dysfunction and myocardial fibrosis. Mechanistically, we found that Musclin enhanced CNP/NPR2/cGMP signaling in cardiomyocytes, which led to improved contractility by inhibition of the cAMP degrading phosphodiesterase (PDE)3 and augmented cAMP/protein kinase A signaling. In addition, Musclin directly acted on cardiac fibroblasts to inhibit their activation. Together, our study indicates the therapeutic potential of targeting interorgan cross-talk during heart failure, for example by counteracting the impaired secretion of the Musclin from wasting skeletal muscle.
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| Overall design |
At the age of 8 weeks C57Bl6 mice were exposed to transverse aortic constriction (TAC) around a 27 gauge needle or sham surgery. 12 weeks after surgery, the experiment was terminated and RNA was extracted.
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| Contributor(s) |
Heineke J, Kattih B, Cordero J |
| Citation(s) |
35013221 |
| |
| Submission date |
Apr 02, 2019 |
| Last update date |
Jan 28, 2022 |
| Contact name |
Joerg Heineke |
| E-mail(s) |
Joerg.Heineke@medma.uni-heidelberg.de
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| Organization name |
Medizinische Fakultät Mannheim
|
| Department |
– Department of Cardiovascular Research (HKF)
|
| Street address |
Ludolf-Krehl-Str. 7-11
|
| City |
Mannheim |
| State/province |
Baden Wuttemberg |
| ZIP/Postal code |
68167 |
| Country |
Germany |
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| Platforms (1) |
| GPL17021 |
Illumina HiSeq 2500 (Mus musculus) |
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| Samples (9)
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| Relations |
| BioProject |
PRJNA530525 |
| SRA |
SRP190154 |
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