Muscles are vital for everyday human life. Skeletal muscle contractions enable us to move, stop, and stay upright. Without these complex fiber-like cells, voluntary functions, including swallowing and speaking, would be impossible. At the same, our ability to pump blood, a life-sustaining involuntary function, is only possible because of the cardiac muscle that enables our hearts to contract.
Impairments to skeletal muscle or cardiac muscle can lead to problems with specific organs or entire systems. The impact is often devastating. Muscle diseases, like Duchenne Muscular Dystrophy, while rare, can severely limit mobility and, in some cases, reduce life expectancy dramatically. While new therapies offer hope, there are no cures for these diseases.
Not surprisingly, researchers in labs at UW Medicine and across the University of Washington are keenly interested in skeletal and cardiac muscle biology; the implications for the treatment of muscular dystrophy, heart diseases, and other rare and widespread diseases could be profound. Yet, until recently, there was no centralizing force to connect muscle investigators.
Now, a new center at the UW Medicine South Lake Union campus is forming to fill that void. Funded by a five-year $4.3 million Center Award from the National Institute for Arthritis, Musculoskeletal, and Skin Diseases (NIAMS), the Center for Translational Muscle Research (CTMR) will enable researchers to accelerate and expand skeletal muscle research, facilitate novel insights into muscle pathologies, and move therapeutics toward the clinic and the marketplace.
Dr. Mike Regnier, the UW Washington Research Foundation Professor of Bioengineering and an investigator at the UW Medicine Institute for Stem Cell and Regenerative Medicine (ISCRM), will lead the center.
“The idea for the center came from years of collaboration within the muscle research community,” says Regnier. “We saw a need for a way to bring people together, to pull in new professors and postdocs, and to offer them tools, facilities, and expertise. We want to be a world-class center and make real contributions to human medicine.”
The new center comes into existence at an exciting time for muscle research. Regnier, and two of his colleagues – Dr. Jeff Chamberlin and Dr. David Mack – are all linked to several promising new treatments for muscle diseases, including a groundbreaking gene therapy that is giving young boys with Myotubular Myopathy the ability to walk.
The Senator Paul D. Wellstone Muscular Dystrophy Cooperative Research Center is a primary driver of hope and progress in the field of muscle research. Led by ISCRM researcher Dr. Jeff Chamberlain, and Dr. Stephen Tapscott, of the Fred Hutchinson Cancer Research Center, the Wellstone Center is currently developing the clinical infrastructure necessary for future gene therapy trials in Duchenne and facioscapulohumeral dystrophies.
Indeed, the muscle center will overlap with labs across the UW Medicine South Lake Union campus. Within ISCRM, for example, investigations centered on basic muscle biology, disease modeling, and drug discovery will gain new energy and new direction from the resources housed at the CTMR.
The NIH/NIAMS grant is funding several cores within the CTMR, giving the Center and its researchers the devices, analytic tools, and the infrastructure to accelerate translational discoveries with next-level speed and accuracy, and to delve deeper into the muscle defects underlying muscle diseases.
First, a mechanical device core will lower two critical barriers for researchers who want to produce data requiring sophisticated equipment: skill and money. “The grant helps us to purchase and maintain instrumentation and staff the core with technicians who know how to run it,” explains Mack, a member of the team behind the NIH/NIAMS grant. Among the outcomes, he says, are greater operating efficiency for labs and more consistent – intercomparable – data, giving researchers unprecedented insight into muscle biomechanics at all levels, from proteins to organs.
Second, a metabolism core, led by Dr. Dan Raftery, a professor in Anesthesiology & Pain at UW Medicine, will enable researchers to explore the interplay between metabolism and muscle mechanics with vastly increased precision. According to Regnier, “Metabolomics and muscle contraction have to be studied together. In the heart, for example, a lack of fuel can affect the contractile apparatus of muscle. Bigger picture, the metabolism core will let us step up our analysis of metabolomics, energetics, cell respiration, and mitochondrial function.”
Third, the quantitative analysis core, led by Dr. Tom Daniel, a professor in Biology, will provide the muscle research community with computational statistical tools to analyze large data sets, model protein, cell, and muscle functioning, develop predictive tools, and understand the best targets for therapeutic application. “We can take observations at the smallest levels, scale them up, and see things we never would have predicted, then make new predictions,” says Regnier, who characterized the approach as “disease-in-dish, except on a computer. “There’s huge potential to reduce the cost of developing new therapeutics,” he adds.
The CTMR will offers pilot grants for young investigators looking to fund their own research projects – advancing the center’s mission to provide training and, ultimately, attract additional grants that will create a flywheel effect for ISCRM and the UW.
Another precious resource, of course, is time. “That’s one of the most important benefits of the center,” says Mack. “The CTMR will accelerate everything we do. It’s a game-changer for investigators to be able to access these services without having to stop and figure out how to pay for it. We’re also going to see integrated data flowing at full speed between the cores, which is extremely uncommon. It just clears the path forward for all of us.”
“Having access to the diverse expertise and innovation within each of these cores will be a major catalyst for our lab,” says Dr. Jennifer Davis, an assistant professor in Pathology and Bioengineering at UW Medicine, and an ISCRM researcher.. “My lab investigates novel genetic approaches to improve muscle function and prevent maladaptive remodeling and access to the CTMR’s cores will give us entirely new predictive power regarding which genetic signals to manipulate for improving functional outcomes and unprecedented new mechanical and metabolic insights regarding how these targeted genetic manipulations are impacting diseased muscle.”
The perks of creating a world-class muscle center at the UW Medicine South Lake Union campus will extend beyond this research hub community. The NIH/NIAMS grant also provides capacity for CTMR to advise on preclinical development and commercialization of therapies, a major hurdle for researchers. The resources housed at the new center will be available to other research institutions, including the Fred Hutchinson Cancer Research Center, the Allen Institute for Cell Science, and Seattle Children’s Research Institute.
Even the general public stands to benefit. Seminar series, workshops, and training opportunities will enable the community to learn more about muscle research happening at the UW Medicine South Lake Union campus and neighborhood – building on ISCRM’s ongoing public events and tours focused on broader topics related to stem cell and regenerative medicine research.
For ISCRM, sharing the UW Medicine South Lake Union campus with the new muscle center is a symbiotic relationship that sets both entities up for collaborative impact. UW Medicine researchers will use the Muscle Center to investigate a wide range of muscle disorders, from rare conditions, to well-known diseases, including ALS. The Muscle Center will be a world leader in growing human stem cells into skeletal and cardiac muscle tissue, creating disease-in-a-dish models to expand knowledge about how muscle diseases begin and to accelerate the effort to develop therapies for patients
The progress in Duchenne Muscular Dystrophy is one proof point, says Regnier “In DMD, patients [always boys] are missing the protein dystrophin, which was not thought to be involved in muscle contraction. But using stem cells derived from patient tissue and turned in to cardiac and skeletal muscle cells, we saw that not having this protein had a profound impact on contraction, which means respiratory muscle cells can’t assist in breathing and the heart is challenged to pump enough blood to meet the body’s demands. Having these stem cells – and access to stem cell experts – gave us the Aha moment – that there are structural deficits with big functional implications. The problem goes deeper than skeletal muscle.”
Regnier cites David Mack as one of the experts who can harness stem cells into tools for discovery and treatment for muscle diseases like DMD. “David is one of the people on the leading edge of that work. One of the benefits of being at South Lake Union is we have so many investigators with knowledge and expertise that can be directly applied to muscle research. That’s an advantage we have that a lot of other people and places don’t have.”
News that Mack and his colleagues will be using stem cells to advance muscle research is already reverberating outside the lab. Former Husky football player Phil Green, who was diagnosed with ALS in August 2018, referred to UW’s entry into the fight against the disease, fantastic. “I think stem cells are going to help us accelerate research. The exciting thing to me is we can use stem cells to recreate the neuromuscular system in a dish, then we’ll be able to identify potential therapies.”
Green is particularly energized by the collaborative nature of the Muscle Center. “They are bringing fresh eyes to the problem and using their expertise to consider new solutions to solve the ALS puzzle,” says Green. “They are leveraging their experience in muscle biology and bioengineering in a collective way to try creative approaches, like muscle systems on a chip.”
It hasn’t taken long for the UW School of Medicine researchers to leverage the NIH funding for the CTMR into new opportunities. Regnier and Mack are part of a five-year, $10 million collaborative grant funded by the National Institute for General Medical Science (NIGMS). The research team, which unites investigators from Stanford University, the University of California Santa Barbara, and the Curie Institute in Paris, will use hypertrophic cardiomyopathy (HCM) as a model to study how subtle changes in the protein myosin can lead to alterations – and ultimately, health problems – at the cellular and tissue levels.
Local partnerships will enable researchers in the CTMR to create direct connections to patients. The center is collaborating with two clinicians on the front lines of medicine, Nassim Rad, MD, who practices at the UW Medical Center Rehabilitation Medicine Clinic and Mike Bamshad, MD, chief of the Division of Genetic Medicine in the Department of Pediatrics at the UW School of Medicine.
As a result, patients will be able to contribute to scientific and medical research by donating biopsy tissue and cells, and CTMR researchers will have pathways in place to bring new therapies to patients as they become available.
“The new muscle center offers patients with muscular dystrophy something they have not had in a long time—hope,” says Rad. “For many years optimal treatment focused on symptom management in order to maintain function, but the investigational research at the muscle center allows clinicians to discuss novel treatments with patients. These patients are racing against time due to the progressive nature of their diseases and the ability of the muscle center to accelerate therapeutic trials is profound.”