The myosuppressin structure-activity relationship for cardiac contractility and its receptor interactions support the presence of a ligand-directed signaling pathway in heart.

The structural conservation and activity of the myosuppressin cardioinhibitory peptide across species suggests it plays an important role in physiology, yet much remains unknown regarding its signaling. We previously reported Drosophila melanogaster myosuppressin (dromyosuppressin, DMS; TDVDHVFLRF-NH2) decreases cardiac contractility through a G protein-coupled receptor, DMS-R2. Our study showed the DMS N-terminus amino acids influence its structure-activity relationship (SAR), yet how they act is not established. We predicted myosuppressin N-terminal amino acids played a role in signaling. Here, we tested our hypothesis in the beetle, Zophobas atratus, using a semi-isolated heart bioassay to explore SAR in a different Order and focus on cardiac signaling. We generated a series of myosuppressin truncated analogs by removing the N-terminal residue and measuring the activity of each structure on cardiac contractility. While DVDHVFLRF-NH2 decreased cardiac contractility, we found VDHVFLRF-NH2, DHVFLRF-NH2, and HVFLRF-NH2 increased activity. In contrast, VFLRF- NH2 decreased activity and FLRF-NH2 was inactive. Next, we analyzed molecular docking data and found the active truncated analogs interacted with the 3-6 lock in DMS-R2, the myosuppressin cardiac receptor, disrupting the salt bridge between H114 and E369, and K289 and Q372. Further, the docking results showed the inhibitory effect on contractility may be associated with contact to Y78, while the analogs that increased contractility lacked this interaction. The data from our study demonstrated N-terminal amino acids played a role in myosuppressin activity and signaling suggesting the cardiac receptor can be targeted by biased agonists. Our myosuppressin cardiac contractility data and predicted receptor interactions describe the presence of functional selectivity in a ligand-directed signaling pathway in heart.

Etiologic factors associated with selected running injuries.

The purpose of this study was to determine whether a relationship exists between selected biomechanical, anthropometric, and training variables and runners afflicted with one of the following injuries: iliotibial (IT) band friction syndrome, shin splints, and plantar fasciitis. Competitive and recreational runners were divided into a non-injured control group (N = 19), an IT band friction syndrome injury group (N = 13), a shin splint injury group (N = 17), and a plantar fasciitis injury group (N = 15). Discriminant function analysis of the biomechanical data revealed two significant (P less than 0.05) discriminators between the control and shin splint groups; maximum pronation velocity and maximum pronation. Analysis of the anthropometric and training data revealed that plantar flexion range of motion was a significant (P less than 0.05) discriminator between the control and plantar fasciitis groups. In addition, analysis of the descriptive statistics (mean +/- SE) identified some non-significant (P greater than 0.05) trends between the injury and control groups: maximum pronation, total rearfoot movement, and maximum velocity of pronation were greater in the injury groups; the injury groups showed a trend toward a higher arch; dorsiflexion range of motion was less in the shin splint group; a greater percentage of injured runners had a leg length difference (greater than 0.64 cm); 20% more runners in the injury groups ran hills; and 20% more of the runners in the IT band friction syndrome group ran on crowned roads.