BPS2022 was dense with great talks in muscle research, but these were my top five favorites:
Truncations of MYBPC are associated with cardiomyopathies--this is expected as MYBPC is a key regulator of muscle contraction and force. However, Valentin Burkart showed us that MYBPC truncation mutations don’t have time to specifically influence the regulation of the sarcomere because their corresponding mRNA is almost entirely degraded before translation (nonsense-mediated degradation). Valentin's results suggest that haploinsufficiency is primarily responsible for muscle dysfunction rather than a misbehaving MYBPC.
Considering how long MYBPC and its mutations have been studied, I found it surprising that nobody before Valentin had investigated this. Are we investing good time in studying certain mutations of any disease-associated protein in detail when they don't even make it to protein expression? Knowing how the mutant misfolds or interacts may not be the best use of research efforts when it is not expressed at the protein level! Perhaps Valentin's approach should be an early step in investigating newly identified mutations.
Of course, MYBPC is not the only regulator at the thick filament. Muscle myosin II can adopt an autoinhibited state: heads stick together and dock onto subfragment 2. Docked heads can't participate in contraction and they are associated with very low ATPase activity (the super-relaxed state, SRX). Mutations in myosin that cause hypertrophic cardiomyopathies generally interfere with head-head binding or head-S2 docking and discourage an SRX.
Neha Nandwani shared a couple of mutations that still disrupt the SRX even though their locations aren't part of any head-head or head-S2 interfaces. Neha called our attention to myosin's incredible allostery with ATPase assays, in vitro motility, and intrinsic force measurements. Is the myosin SRX always caused by structural autoinhibition or can other factors bring myosin to an SRX? Neha's talk reminded me that, despite numerous studies, the answer remains less clear than we are prone to remember as we talk of the SRX and head-S2 docking interchangeably.
Along with the SRX, and perhaps because of it, there was a lot of attention on dATP/dADP at this year's meeting. Matt Childers showed us how dADP influences a mutant myosin's structure based on detailed molecular dynamics studies. Matt focused on a dilated cardiomyopathy mutation (A223T) which does not interact with the nucleotide as much as wild-type myosin does. Along with other differences, the mutant myosin also differs from the wild type in the structure of its actin binding site. Replacing ADP with dADP in the mutant myosin model reversed some of its structural differences from the wild type.
I'm eager to see how cry-EM or crystal structures of dADP-myosin compare to the MD studies. We are seeing more and more functional data around dADP but it was great to see some detailed structural models beginning to tease out how such a small chemical difference can create such a large functional difference!
Speaking of small chemical differences, Anne Houdusse delivered some incredible examples of them. Anne showed us several really useful structures of drug-bound myosins. In doing so, she revealed that two drugs causing entirely opposite effects on contractility can bind to the same exact site. Anne provided a new angle for looking at binding specificity. I tend to think of specificity in terms of structure, but I am reminded that there is a functional element to specificity also… and it might just be a few noncovalent interactions that make all the difference.
Lastly, Máté Gyimesi presented a new drug candidate for adjusting skeletal muscle contraction, MPH-220. Máté walked us from the drug design process to in vitro tests to MPH-220's amazing specificity for fast skeletal muscle and all the way to mouse studies. My favorite part of any of this year's talks was watching his videos of MPH-220 in action. They spoke for themselves and they spoke encouragement: this stuff really can work! I watched the mouse walking comfortably without falling or stumbling and thought of all the people in the future whose lives will be easier because of this drug--because of the people who have invested their work and their minds into creating it. Research really can make a difference, y'all.
What was your favorite talk of BPS2022? Let me know in the comments!