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Impact of Muscle Physiology Research on Common Diseases and Disorders Roundtable
Friday, December 16, 2011
NIH Campus, Building 31, Room 6C10
9:00 AM — 4:00 PM
The overall goal of all NIAMS roundtables is to discuss scientific and clinical needs and opportunities, and to listen to the concerns and challenges facing the scientific community. These sessions provide a valuable source of input for the NIAMS planning process. This specific roundtable focused on mechanisms of muscle physiology that may contribute to understanding the causes of common diseases and disorders affecting the musculoskeletal and other organ systems. These can include conditions of muscle loss, muscle pain, metabolic syndrome, and diabetes. The discussion explored discoveries in skeletal muscle physiology that are ripe for translation for treatment and prevention, and any gaps in knowledge that, if filled, could advance studies of common diseases.
The NIAMS supports investigations in basic muscle biology and physiology, such as mitochondrial biogenesis, turnover, and function; mechanisms of muscle excitation/contraction coupling; thermogenesis and metabolism; and integrated physiology of muscle with other organ systems. In addition, the NIAMS muscle research portfolio includes projects addressing atrophy, cachexia, sarcopenia, muscle fatigue, heat illness, and muscle pain. Some of these conditions are also areas of emphasis for other NIH Institutes and Centers (ICs). While NIAMS supports research aimed at understanding the mechanisms of these conditions as they relate to muscle physiology, the other ICs more frequently support clinical studies and clinical trials.
In advance of the meeting, participants were encouraged to consult with colleagues on the following questions:
- What are the most promising areas of science, within or outside of your field of research?
- What are the most pressing scientific needs in muscle biology, such as technologies, animal models, research infrastructure, etc? Are there adequate collaborative efforts, support for building research teams, and ways to enhance communication within and among research fields?
- What are the current translational opportunities in muscle physiology research? Examples of translational opportunities could include druggable targets, candidate biomarkers of disease, animal models of diseases or conditions, etc. What led to these opportunities? Are there lessons to be learned about common features of basic research strategies that lead to translatable discoveries?
- Diseases and conditions, such as musculoskeletal atrophy, metabolic syndrome, diabetes, age-associated sarcopenia, cachexia (associated with chronic heart failure, sepsis, severe burns, HIV/AIDS, and other disorders), debilitating muscle fatigue, and heat illness all involve perturbations to normal skeletal muscle physiology. Are there other diseases and conditions for which prevention or treatment could be advanced by expanded knowledge of muscle physiology? Are there logical priorities for muscle physiology studies relative to these conditions?
- What are the gaps in our understanding of muscle physiology that are the largest or need to be filled most urgently? How could progress in the prevention or treatment of diseases or disorders be accelerated by filling these knowledge gaps?
- Taking diversity into account, what innovative, creative approaches are needed to transform the understanding of health disparities, and improve representation of minority researchers?
- How can the research enterprise be more efficient? How can we have the greatest impact on scientific advances and public health in times of fiscal constraint?
Although only a subset of these topics were discussed in depth at the meeting, NIAMS leadership and the appropriate program staff read each comment. The NIAMS greatly appreciates the community’s input on these questions.
Importance of Advancing Knowledge of Muscle Physiology
Participants in the discussion emphasized the importance of scientific opportunities to understand the mechanisms of muscle loss common to several conditions, including cachexia (loss of skeletal muscle associated with other organ disease), disuse atrophy, and sarcopenia (age-related loss of skeletal muscle tissue). Although these conditions result from diverse initiating causes, they may share etiologic pathways and outcomes (mitochondrial dysfunction, contractile dysregulation, cell membrane weakness, etc.), and may respond to the same treatments. Continued effort should be focused on understanding the regulation of muscle protein and organelle degradation through the ubiquitin proteasome system, as well as through autophagy.
There is a need for a more thorough understanding of the regulation of muscle loss by inflammatory and immune factors. Glucocorticoids and inflammatory cytokines may be key regulators of muscle loss in many conditions. The role of macrophages in muscle degeneration and regeneration is a promising area of research. It is important to regard muscle as a store for essential amino acids, and that the increased degradation of muscle protein supplies the amino acid needs of other organs. Further study of the regulation of muscle protein synthesis and degradation, and how these processes are linked, will contribute to an understanding of the mechanisms of muscle loss and may uncover novel targets for treatments.
The epigenetic determinants of muscle function and dysfunction have not been well characterized. They may have a significant role in common disorders associated with muscle loss and may provide opportunities for strategies in personalized medicine. Participants considered further studies of muscle epigenetics to be warranted because upregulation of deacetylases has been seen in muscle atrophy and sarcopenia. Some meeting attendees speculated that progress in muscle epigenetics may be limited by the availability of reliable tools.
The importance of muscle as a sensor and integral effector of the central nervous system (CNS) was discussed at the meeting. It is estimated that as much as 80% of brain activity is devoted to communication with muscle. Spinal cord injury and peripheral nerve damage lead to muscle loss. On the other hand, maintaining muscle mass after nerve injury may promote nerve regrowth. Recent studies suggest that there is extensive communication between muscle and bone via the nervous system. Further study of the interactions of muscle and nerve cells through ion and protein signals may lead to novel targets for the treatment of common conditions.
Another emerging area of research discussed at the meeting was the role of muscles as endocrine and paracrine organs. Participants were in agreement that myokines, secreted by muscle especially in response to exercise, are likely to be important in the integration of muscle with other tissues and organs, such as adipose tissue, bone, and liver. These interactions could be critical for health outcomes. Participants pointed out that differences in secreted proteins from different fiber types have not been well characterized and may be quite informative. Strategies for targeting muscle to address the effects of diseases in other organs hold great promise. There is a need to better understand the relationship between increased muscle mass, and resistance to diseases of other organs.
The participants in this meeting also expressed the need for additional studies of skeletal muscle and exercise. Because exercise and nutrition both promote increases in muscle mass, the interplay of these stimuli is an important focus of research. The effects of exercise on mitochondrial biosynthesis and the impact of muscle mitochondria on systemic health are considered fertile areas of investigation. Participants expressed concern that the tools available for the study of mitochondrial function may be limiting progress in this area, and that techniques currently used to study mitochondria could be misleading. Further study of the function of mitochondria in healthy and diseased muscle and during aging is needed, along with sensitive and reproducible approaches for the study of these organelles.
The function of active, exercising muscle has been revealed by a large body of research, but not much is known about energy expenditure and thermogenesis in resting muscle. The mechanisms of resting muscle adenosine triphosphatase (ATPase) activities have not been fully characterized, and the predominant “furnace” of skeletal muscle has not been identified, but participants at the meeting described several intriguing possibilities. A conformation of thick filament myosin called the super relaxed state has been described, and the relative proportion of myosin heads in this state could significantly affect the basal rate of energy expenditure and heat production. The sarcoplasmic reticulum and mitochondria may be other sites of heat production in skeletal muscle. Skeletal muscle and brown adipose tissue both exhibit mitochondrial uncoupling as a mechanism for generating heat, and a molecule secreted by muscle promotes thermogenesis in adipocytes. Insights into the regulation of this process could lead to therapeutics for obesity, metabolic syndrome, or other conditions.
Many important advances have come from research on muscle in isolation; however, there is a need for more integrative physiology studies, such as muscle’s part in releasing endocrine/paracrine factors, the effects of muscle on bone and other tissues via the nervous system, the impact of muscle on the immune system, and vice verse, and understanding muscle-tendon and muscle-vasculature interactions.
Translational Research Opportunities in Muscle Physiology
The current base of knowledge sets the stage for understanding the place of muscle in common diseases and disorders. Factors affecting muscle condition, such as mitochondrial health, can influence outcomes, lifespan, and survival. Biomarkers and other outcome measures of muscle status, disease, and response to therapy are needed. Because muscle quality is more important than muscle size, tools for this assessment can be developed. Basic science discoveries may yield useful biomarkers through metabolomics, gene expression analyses, magnetic resonance spectroscopy, and other approaches.
Important translational opportunities can arise from better understanding of the unintended side effects of certain drugs on muscle. For example, statin-induced myopathies and corticosteroid-induced loss of muscle mass are two conditions with significant public health implications. Elucidation of the pathogenic mechanisms will provide insights into predicting, treating, and potentially preventing these conditions.
Promising targets for pharmacologic modulation are also emerging for regulating muscle mass and function. For example, increasing mitochondrial biogenesis may promote resistance to muscle fatigue and increase resting energy expenditure, as a strategy to reverse obesity. Advances in understanding regulation of fiber type and mitochondrial biogenesis have provided exciting targets for therapy development. For example, mice that produce large amounts of the muscle-specific molecule PGC1a are more resistant to exercise-induced fatigue and aging-related effects. Inhibitors of the myostatin pathway (a protein that counteracts muscle growth) may be potential treatments for a variety of conditions involving loss of muscle mass, and they have been shown to maintain muscle mass in mouse models of cancer cachexia. Androgen receptors on muscle cells may also be selective targets for preserving muscle integrity. Strategies to modulate energy expenditure and thermogenesis in resting muscle could be applied to address obesity or metabolic syndrome. All of these discoveries related to the physiology of muscle provide opportunities for the development of novel therapies for the treatment of common disorders.
Critical Gaps in Knowledge
Participants discussed many critical gaps in our knowledge of skeletal muscle physiology that, when filled, could lead to better understanding of the etiology of common conditions and to novel treatments. These include the:
- pathways of muscle wasting and atrophy, for example, the crosstalk of protein synthesis and breakdown;
- mechanisms of insulin resistance;
- potential roles of epinephrine, leptin, and thyroid hormone in thermogenesis; and
- communication of skeletal muscle with other tissues and organ systems, and the effects of these interactions on health and disease.
There is a need for biomarkers of biochemical pathways in skeletal muscle to quickly evaluate the impact of experimental drugs that affect muscle growth or function.
Skeletal muscle fatigue is a common symptom, but the etiology is not understood. Without a standardized definition for skeletal muscle fatigue, it has been difficult to make advances on this important topic. Furthermore, there are many potential causes, including decreased excitability of the sarcolemma, depletion of calcium ion stores, buildup of reactive oxygen species or phosphate, and changes in CNS activation of motor units, which makes studying fatigue quite challenging.
Scientific Needs and Challenges
There is a need for better animal models to recapitulate human diseases and conditions related to muscle physiology. In addition, standardization of animal models would improve the reproducibility of study findings. Mice and other rodents are the most common research species in current use, but non-mammalian systems, such as fish, frogs, and flies, may also yield important insights. Cultures with mixed cell types (muscle, nerve, fat, endothelium, etc.) could be good models for studying muscle interactions with other organ systems. Sharing resources, such as mice, well-characterized muscle cell lines from patients with various conditions, clinical samples, and bioinformatics data would not only facilitate this standardization, but would also improve the efficiency of research through the utilization of existing materials and information. Specialized scientific resources will also accelerate progress, such as physiologic testing of mouse models and proteomics tools that overcome the abundance of contractile proteins in cell lysates.
Multidisciplinary collaborations are cited as essential to current research efforts in integrative physiology affecting muscle biology and function. Interdisciplinary meetings that bring together muscle biologists and physiologists with scientists from other fields, such as immunology, neuroscience, obesity, skeletal biology, and aging, would facilitate interactions. The American Society for Bone and Mineral Research is beginning to organize more sessions related to muscle physiology (for example http://www.asbmr.org/Meetings/TopicalMeetings.aspx). Disease-oriented conference themes draw more participation from industry and patient groups. The NIAMS and other NIH ICs have provided sponsorship for such meetings, and are likely to continue this activity.
More collaboration between scientists and clinicians would make basic science more relevant to human health, and advance the impact of muscle physiology research on common diseases and disorders. Thus, there could be better correlation between specific muscle phenotyping in the laboratory with clinical conditions, and basic research with the identification of therapeutic targets. Standardized phenotyping of muscle diseases and conditions would also benefit the translation of many laboratory findings. In addition, communication between academic research scientists and scientists in industry may make the transition from basic and translational research to clinical research smoother.
Conducting science under fiscal constraints requires a change in strategy to maintain the momentum of new discoveries. New investigators are seen as particularly vulnerable in the current budget climate, and retaining them in biomedical research careers is a growing concern. More attention to good mentorship, which can involve a multidisciplinary team, will support their professional development and progression. Pilot grant funding, grantsmanship training, and guidance in understanding the NIH funding process are also important tools for early career researchers.