BPS2026 - Myosin binding protein-C’s (MyBP-C) role in regulating cardiac and skeletal muscle responses to rapid stretch

Myosin binding protein-C (MyBP-C) consists of a family of regulatory proteins with unique paralogs that are differentially expressed in sarcomeres of cardiac, fast-twitch, and slow twitch skeletal muscles. The 3 MyBP-C paralogs are encoded by separate genes but maintain an overall similar structure, although sequence homology is significantly different. Here, we explored functional effects of the 3 paralogs by making use of our cut and paste approach to remove and replace MyBP-C in sarcomeres of different muscle types, namely cardiomyocytes, slow-twitch soleus muscle, and fast-twitch psoas muscle. Removal of MyBP-C led to a reduction of Ca 2+ -sensitivity in cardiac and fast-twitch skeletal muscle, while Ca 2+ -sensitivity appeared unchanged in slow-twitch muscles. However, all three fiber types showed increases in crossbridge cycling rates following a rapid slack-restretch maneuver ( k tr ). Removal of MyBP-C also produced spontaneous oscillatory contractions (SPOC) at submaximal calcium concentrations in each muscle type. However, we found that responses to rapid stretch in activated muscle, which provide a measure of crossbridge attachment and detachment rates, varied for each muscle type. This was most obvious in fast-twitch fibers, where loss of MyBP-C conferred stretch activation-like responses following MyBP-C removal, something typically not seen in fast-twitch fibers. Furthermore, addition of recombinant fast MyBP-C and slow MyBP-C into cardiomyocytes reduced or eliminated stretch activation responses typically seen in cardiomyocytes. These data indicate that MyBP-C paralogs alter transient responses to stretch in each muscle type suggesting that MyBP-C uniquely contributes to the kinetics of myosin crossbridge cycling in different muscles.