Biology subjects

Matinmehr, F.

Publications and source records attributed to Matinmehr, F..

2 recordsLinked to original sources

bioRxiv2022

Myosin essential light chain 1sa decelerates actin and thin filament gliding on β-myosin molecules

The {beta}-myosin heavy chain expressed in ventricular myocardium and the myosin heavy chain (MyHC) in slow-twitch skeletal soleus muscle type-I fibers are both encoded by MYH7. Thus, these myosin molecules are deemed equivalent. However, some reports suggested variations in the light chain composition between soleus and ventricular myosin, which could influence functional parameters such as maximum velocity of shortening. To test for functional differences of the actin gliding velocity on immobilized myosin molecules we made use of the in vitro motility assay. We found that ventricular myosin moved actin filaments with approx. 0.9 m/s significantly faster than soleus myosin (0.3 m/s). Unregulated actin filaments are not the native interaction partner of myosin and are believed to slow down movement. Yet, using native thin filaments purified from soleus or ventricular tissue, the gliding velocity of soleus and ventricular myosin remained significantly different. When comparing the light chain composition of ventricular and soleus {beta}-myosin a difference became evident. Soleus myosin contains not only the "ventricular" essential light chain (ELC) MLC1sb/v, but also an additional longer and more positively charged MLC1sa. Moreover, we revealed that on a single muscle fiber level, a higher relative content of MLC1sa was associated with significantly slower actin gliding. We conclude that the ELC MLC1sa decelerates gliding velocity presumably by a decreased dissociation rate from actin associated with a higher actin affinity compared to MLC1sb/v. Such ELC/actin interactions might also be relevant in vivo as differences between soleus and ventricular myosin persisted when native thin filaments were used. SummaryCompared to the "ventricular" essential myosin light chain MLC1sb/v, the longer and more positively charged MLC1sa present in slow-twitch soleus muscle fibers decelerates actin filament gliding on {beta}-myosin molecules presumably by a decreased dissociation rate from actin filaments.

physiology↗

bioRxiv2020

Identification of MYOM2 as a candidate gene in hypertrophic cardiomyopathy and Tetralogy of Fallot and its functional evaluation in the Drosophila heart

The causal genetic underpinnings of congenital heart diseases, which are often complex and with multigenic background, are still far from understood. Moreover, there are also predominantly monogenic heart defects, such as cardiomyopathies, with known disease genes for the majority of cases. In this study, we identified mutations in myomesin 2 (MYOM2) in patients with Tetralogy of Fallot (TOF), the most common cyanotic heart malformation, as well as in patients with hypertrophic cardiomyopathy (HCM), who do not exhibit any mutations in the known disease genes. MYOM2 is a major component of the myofibrillar M-band of the sarcomere and a hub gene within interactions of sarcomere genes. We show that patient-derived cardiomyocytes exhibit myofibrillar disarray and reduced passive force with increasing sarcomere lengths. Moreover, our comprehensive functional analyses in the Drosophila animal model reveal that the so far uncharacterized fly gene CG14964 may be an ortholog of MYOM2, as well as other myosin binding proteins (henceforth named as Drosophila Myomesin and Myosin Binding protein (dMnM)). Its partial loss-of-function or moderate cardiac knockdown results in cardiac dilation, whereas more severely reduced function causes a constricted phenotype and an increase in sarcomere myosin protein. Moreover, compound heterozygous combinations of CG14964 and the sarcomere gene Mhc (MYH6/7) exhibited synergistic genetic interactions. In summary, our results suggest that MYOM2 not only plays a critical role in maintaining robust heart function but may also be a candidate gene for heart diseases such as HCM and TOF, as it is clearly involved in the development of the heart. SUMMARY STATEMENTMYOM2 plays a critical role in establishing or maintaining robust heart function and is a candidate gene for heart diseases such as hypertrophic cardiomyopathy and Tetralogy of Fallot.

genetics↗