Stephen I. Katz, M.D., Ph.D., NIAMS
Glen Nuckolls, Ph.D., NIAMS
Paul Allen, M.D, Ph.D., Brigham and Women's Hospital
Introduction and Background
The NIAMS supports research, training, and career development in areas that yield insight into muscle biology and diseases. Support for infrastructure such as patient registries facilitates research funded by NIH and other public and private organizations. The topic of the roundtable, "Muscle Biology and Diseases," includes two scientific programs at NIAMS:
- Muscle Development and Physiology
- Muscle Disorders and Therapies
The discussion expanded on the feedback compiled by participants, as well as input submitted via a Web-based Request for Comments. In particular, panel members focused on what they viewed to be the most promising areas of science and pressing basic, translational, and clinical research needs.
During the meeting, participants emphasized the need for continued research on basic mechanisms of muscle development, growth, maintenance, physiology, pathology, and regeneration. Studies of protein:protein interactions and complex formation, for example, may provide valuable information about the mechanisms of force generation and excitation-contraction coupling. Little is known about associations between changes in muscle with maturity, and the mechanisms underlying differences in disease progression and in responses to treatments at different ages. The role of circadian rhythms in skeletal muscle is another emerging field.
Many genetic and acquired muscle diseases display similar downstream pathologies, such as weakness and wasting, and may share signaling pathways that small molecules could target. Muscle pain, or myalgia, is another symptom needing more research into the causes, prevention and treatment.
Although many of the diseases of muscle are single gene defects, genome-wide association studies (GWAS) and systems biology strategies offer opportunities to better understand the genetic basis for difference in response to treatment. GWAS also can help to identify genes associated with more common muscle disorders, such as age-related sarcopenia, weakness, and fatigue. Furthermore, understanding epigenetic modifications and post-translational processing should reveal additional therapeutic targets. GWAS and other tools may be useful in the study of rare and common muscle diseases and disorders.
Participants emphasized the need to study muscle as an organ system that interacts with other tissues and organs. Factors released by muscles during exercise can have a significant effect on the immune system, brain and other organs. Many who suffer from non-muscle diseases, including cancer and heart disease, experience skeletal muscle loss and weakness. This can be further exacerbated by prolonged bed rest (often in the context of critical illnesses), which causes degeneration of both muscle and bones. And, understanding the metabolic and hormonal interactions between muscle, bone, and fat at rest and during activity likely will answer questions related to the association between lean body mass, reduced mortality and increased quality of life.
Progress toward clinical trials in muscle diseases is limited by the availability of effective early biomarkers that are predictive of subsequent changes in physical function. Meeting participants expressed enthusiasm regarding the potential for magnetic resonance imaging (MRI) and spectroscopy (MRS), as well as ultrasound, for detecting and quantifying changes in muscle composition, cellular structure and integrity, and metabolic activity. Participants in the muscle roundtable reiterated points that were raised at an NIAMS 2007 workshop on muscle MRI/MRS, which focused on the need for correlating data from advanced imaging and spectroscopic approaches with outcome measures of muscle function that are important to the patients.
Transplantation of mesenchymal or muscle-derived stem cells was viewed as a promising therapy for muscle diseases, disorders, or conditions such as traumatic injury. Embryonic stem cells or human induced pluripotent stem (IPS) cell lines should be explored as possible therapeutic approaches. Participants mentioned the elucidation of factors governing satellite or stem cell survival, distribution, integration, and differentiation in vivo as promising basic research topics.
Stem cells also were mentioned in the context of effective model systems. IPS cells, for example, might be used for screening therapeutic compounds for individual patients, or for testing findings from animal studies before beginning clinical trials. Participants also discussed the importance of model organisms (zebrafish) and other resources, such as the NIH Molecular Libraries collection and the NIH-RAID Pilot (Rapid Access to Interventional Development) through the NIH Roadmap for Medical Research, for high-throughput screening and other preclinical research activities. Costs associated with developing, maintaining, and studying small and large animal models were another concern.
The basic and translational research communities continue to need access to patient samples and clinical data. As researchers have made great strides in identifying disease-causing mutations that genetic screening can identify, they now are worried about being able to get tissue samples as minimally invasive diagnostic tests replace biopsies.
Strategies to restore defective gene function or to compensate for its loss are showing promise. Building on findings about the molecular defect responsible for myotonic dystrophy, for example, researchers are testing molecules that can alter RNA processing. Other molecular therapies with promise include RNA interference, stop codon readthrough and antisense oligonucleotide-induced exon skipping. Knowledge about the interactions among viral vectors, host cells, and the immune system will advance the field of gene therapy.
Discussion also focused on strategies and tools for improving clinical trial design to best utilize small numbers of patients with rare diseases. Like other researchers, the muscle community is interested in early surrogate markers that can be measured non-invasively, are linked to functional outcomes, and are acceptable endpoints to accelerate the progress of clinical trials.
Participants expressed an interest in effectiveness studies of low-tech interventions such as nutrition, exercise, and physical therapy. Understanding the mechanisms responsible for their therapeutic benefits may lead to treatments that are even more effective and better compliance of patients.
Although muscle researchers are located in different basic science or clinical departments, it remains possible to integrate muscle with other topics through common meetings or training programs. Participants repeatedly discussed the importance of reaching out to potential collaborators in other fields—such as genetics, endocrinology, geriatrics, and cardiology, as well as biophysics, biochemistry, physiology, and cell biology—and the need to interest students and fellows in muscle research.
ALLEN, Paul D., M.D, Ph.D. (Co-chair)
Professor, Department of Anesthesia
Brigham and Women's Hospital
BÖNNEMANN, Carsten G., M.D.
Assistant Professor, Division of Neurology
Children's Hospital of Philadelphia
CAMPBELL, Kevin P., Ph.D.
Neurology Investigator, Howard Hughes Medical Institute
Professor of Physiology and Biophysics
University of Iowa Carver College of Medicine
CANNON, Stephen, M.D., Ph.D.
Professor and Chairman, Department of Neurology
University of Texas Southwestern Medical Center
CLEMENS, Paula R., M.D.
Chief, Neurology Service, Pittsburgh VA Healthcare System
Associate Professor, Department of Neurology
University of Pittsburgh School of Medicine
DIRKSEN, Robert T., Ph.D.
Associate Professor, Department of Pharmacology and Physiology
University of Rochester School of Medicine and Dentistry
ESSER, Karyn A., Ph.D.
Associate Professor, Department of Physiology
University of Kentucky College of Medicine
EMERSON, Charles P., Jr., Ph.D.
Director and Senior Scientist
Boston Biomedical Research Institute
GUTTRIDGE, Denis C., Ph.D.
Associate Professor, Department of Molecular Virology, Immunology, and Medical Genetics
Ohio State University Medical Center
KIMONIS, Virginia, M.D.
Professor of Pediatrics and Chief, Division of Human Genetics and Metabolism
University of California, Irvine Medical Center
MITTENDORFER, Bettina, Ph.D.
Research Associate Professor, Center for Human Nutrition
Washington University School of Medicine
RAFAEL-FORTNEY, Jill A., Ph.D.
Associate Professor, Department of Molecular and Cellular Biochemistry
Ohio State University Medical Center
STEPHENSON, Bradley R., M.A., J.D.
Attorney at Law, PLLC
San Antonio, Texas