In spite of the rich molecular-scale data provided, clinical applications of high-powered synchrotron radiation for skeletal and cardiac muscle physiology - collectively known as muscle small-angle X-ray scattering or (MyoSAXS) - are limited. MyoSAXS is the only technology available that directly images sarcomeric protein organization in live tissue and is used both in fundamental muscle mechanics research and within the drug development pipeline. Unfortunately, most applications still lie in academia where typical use cases involve competitive access reservations months in advance at one of the few synchrotron beamlines in the world equipped for near-physiological biological samples. The main barriers of entry are thus access, long lead times, and a short supply of trained life-science beamline scientists in the field. As biological beamline scientists ourselves, we recognized how strongly these barriers limit hundreds of academic and industry researchers from using X-ray science and so we founded our firm, Accelerated Muscle Biotechnologies, as a science-as-a-service solution specifically for MyoSAXS synchrotron applications and is the foundation of this application. For this Phase I application, we propose to develop MyoSAXS infrastructure at the LiX beamline at Brookhaven National Labs, a synchrotron facility on Long Island NY, initially for academic users who aren't beamline scientists themselves but wish to acquire sarcomeric data and have more flexible requirements on lead times. We will evaluate our advancement by studying the highly relevant mechanism of Mavacamten on muscle, a recent FDA- approved drug for hypertrophic cardiomyopathy that directly suppresses muscle motor function and used MyoSAXS experiments to show its' interactions with sarcomeric proteins. Our long-term vision however is for MyoSAXS to be available for clinical research where hospitals can send skeletal or cardiac muscle biopsies for molecular testing with at most a 1-week lead time. The proposed improvement at Brookhaven focuses on two objectives: 1) to acquire MyoSAXS data comparable in quality to the current gold standard in the field and 2) to develop reproducibility and repeatability (R&R) metrics to standardize data quality across different synchrotron facilities. These objectives are critical necessities for our business strategy to use Brookhaven as an operational base for the multiple healthcare and academic hubs in the northeast regional area and for future work at other synchrotrons. The lessons learned here about data quality and R&R for muscle tissues are generalizable to other biological samples as well, including renal and nervous tissue, and will set the path for further innovations of synchrotron radiation in clinical applications.
Public Health Relevance Statement: Narrative Small-angle X-ray diffraction is a specialized tool that allows for the most direct study of muscle motor proteins in living, functioning cells. However, the research tools used to wield this technology are not yet refined and so do not meet its potential to study diseases or potential treatment strategies. The research conducted in this project will improve this technique and expand access to more research scientists, accelerating the study of muscle in basic science, clinical science, and drug discovery industries. Terms:
