Muscle phenotype of the myostatin mutant Compact mice and myostatin/IGF-I transcript levels in pathological human hearts

Baán Júlia Aliz
Muscle phenotype of the myostatin mutant Compact mice and myostatin/IGF-I transcript levels in pathological human hearts.
[Thesis] (Unpublished)

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Official URL: http://jhc.sagepub.com/content/61/12/889.full

Abstract in foreign language

Myostatin (Mstn) is an important negative regulator of skeletal muscle growth. However, it plays also a crucial role in governing cardiomyocyte growth, heart metabolism and contraction. Our aim was to describe different aspects of Mstn signaling in skeletal muscle and heart tissue. To this end, two different model systems have been used in our experiments: (1) the Mstn mutant Compact (Cmpt)mice and (2) healthy and pathological human hearts. The hypermuscular Cmpt mice carry a 12 - bp natural mutation in the Mstn propeptide, with additional modifier genes being responsible for the phenotype. Muscle cellularity of the fast tibialis anterior (TA) and extensor digitorum longus (EDL) as well as the mixed - type soleus (SOL) muscles of Cmpt and BALB/c mice was examined by immunohistochemical staining of the myosin heavy chain (MHC) proteins. In addition, transcript levels of MHC isoforms were quantified by qRT - PCR. On the other hand, gene expression of Mstn and IGF-I, the two major but mostly counteracting regulators of heart tissue have been investigated in different regions (septum,left and right ventricle s) of healthy or dilated (DCM) and ischemic cardiomyopathic (ICM) patient hearts. A comprehensive qRT -PCR analysis was carried out by measuring the expression of Mstn, its receptor Activin receptor IIB (ActRIIB), IGF-I, IGF-I receptor (IGF-I receptor), as well as microRNA-208, the negative post-transcriptional regulator of Mstn. According to our results all investigated muscles of Cmpt mice were significantly larger compared to wild type characterized by fiber hyperplasia of different grade. Fiber hypertrophy was not present in TA, however, EDL muscles showed specific IIB fiber hypertrophy while the (I and IIA) fibers of SOL muscles wer e generally hypertrophied. Both the fast TA and EDL muscles of Cmpt mice contained significantly more glycolytic IIB fibers accompanied by decreased number of IIX and IIA fibers, however, this was not the case for the SOL muscles. In summary, Cmpt mouse, inspite of its complex genetic background, shows similarities (at least in fast muscles) to Mstn knockout mice in terms of muscle cellularity and glycolytic muscle phenotype, suggesting that the lack of Mstn is responsible for these morphological changes. However, based on the more pronounced hyperplasia in Cmpt fast muscles as well as the different cellularity and oxidative phenotype of Cmpt SOL, additional studies are needed to elucidate the molecular mechanisms of Mstn inactivity and the possible role of modifier genes in Cmpt mice. In our human heart study , we have found that in healthy control hearts the ratio of Mstn/IGF - I signaling was significantly higher in the left ventricle/septum than in the right ventricle. Moreover, Mstn transcript levels were significantly upregulated in all heart regions of DCM but not ICM patients. However, the ratio of Mstn/IGF - I signaling remained increased in the left ventricle/septum compared to the right ventricle of DCM patients (similar to healthy hearts). In contrast, in ICM hearts significant transcript changes were detected mainly in IGF- I signaling. In paralell with these results microRNA -208 showed mild upregulation in the left ventricle of both DCM and ICM hearts.This is the first demonstration of a spatial asymmetry in the expression pattern of Mstn/IGF - I in healthy hearts, which is likely to play a role in the different growth regulation of left vs. right ventricle. Moreover, we identified Mstn as a massively up-regulated gene in DCM but not in ICM as part of potential compensatory mechanisms in the failing heart.

Item Type: Thesis (Doktori értekezés)
Creators: Baán Júlia Aliz
Magyar cím: A miosztatin mutáns Compact egér izom-fenotípusa és a miosztatin/IGF-I mRNS szintjei patológiás humán szívekben
Témavezető(k):
Supervisor
Beosztás, tudományos fokozat, intézmény
MTMT author ID
Mendler Luca
egyetemi adjunktus, SZTE ÁOK Biokémiai Intézet
10028521
Divisions: Doctoral School of Multidisciplinary Medical Sciences
Tudományterület / tudományág: Medicine > Theoretical Medicine
Nyelv: English
Date: 2015. May 19.
Item ID: 2587
A mű MTMT azonosítója: 2920985
doi: https://doi.org/10.14232/phd.2587
Date Deposited: 2015. Apr. 02. 15:47
Last Modified: 2020. Apr. 21. 11:58
Depository no.: B 5985
URI: https://doktori.bibl.u-szeged.hu/id/eprint/2587
Defence/Citable status: Defended.

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