Final Report Summary - SARCOSI (Sarcomere based Signals in Muscle Remodelling)
Socio-economically, Europeans as a developed society face increasing risks that their striated muscle functions will become impaired in the future: First, demographical trends rapidly increase the numbers of citizens above 50 years of age. Secondly, physically inactive lifestyles have become endemic. Both risk factors seem to synergistically enhance each other, thereby causing a slow progressive muscle force loss. This is increasingly becoming a major socio-economic factor in addition to reducing quality of life. At 50 years-of-age only about 1% of the population has a meaningful loss of skeletal muscles, the percentage increases to about 15% prevalence at 70 years of age. This progressive skeletal muscle force loss becomes clinically relevant when reducing mobility in everyday life settings or when preventing a remobilization in hospitals. The term sarcopenia has been introduced for this novel endemic syndrome (greek for “loss of flesh”). To date, no causative interventions for preventing sarcopenia are available while exercise, resistance training and amino-acid rich nutritional supplements are known as effective prevention methods. Mechanistically, the loss of myofibrils is one of the underlying causes of sarcopenia, and therefore pathomechanisms that directly target the myofibril function in our ageing populations. Similarly, in the cardiac muscle, the dysfunction of cardiomyofibrils is increasingly becoming socio-economically relevant in Europe: A progressive loss of cardiac myofibrillar elasticity in elderly patients interferes with normal blood filling during cardiac diastolic relaxation, thus leading to a state called “diastolic heart failure”. Again, as with sarcopenia, underlying risk factors are age, and states correlated with physical inactivity (such as obesity and diabetes, to name a few).
Taken together, defects in myofibril function, both with regards to force production and elasticity are becoming increasingly clinically relevant in our ageing populations. In the past, clinical research on pathological muscle restructuring and wasting is carried out in many different disciplines, including cardiology, pulmonology (for research on diaphragm dysfunctions), sports medicine (for sarcopenia prevention), pediatrics and neurology (for research on neuromuscular hereditary diseases), and gerontology (for addressing remobilization before hospital discharge).
SarcoSi was developed on this background as an innovative research concept to address research fragmentation in our field by putting the sarcomere on the center stage as our common research objective: In SarcoSi, complementary research teams with interdisciplinary expertise have carried out research how in skeletal and cardiac muscle disease settings sarcomeres are affected mechanistically. Our underlying hypothesis in the beginning of the project has been that the sarcomere itself both provides and receives clues from activity and disease states to regulate in turn its status in an autonomous fashion. Finally, we speculated that in turn, sarcomeres provide back signals to the organs to control muscle trophicity (thus the acronym “SarcoSi” for “sarcomeric signaling”).
To achieve our innovative research objectives in SarcoSi in a fast and cost-effective manner, we established a consortium that brought together complementary expertise on an international level. Our vision has been that network expertise should cover the complete range of complexities from the single sarcomere to the patient whose sarcomeric functions are impaired. Therefore in SarcoSi, clinically oriented groups performing studies on patients that have primary defects in their myofibrils (Harvard university) teamed up with groups working on animal disease models for muscle weakness, as well as with basic scientists that focus on single myofibrils to dissect function and structure. Technically, to pave the way to knowledge transfer and innovation within this multidisciplinary setting, research secondments were implemented to bring together the complementary expertise where needed for innovation. Importantly, this secondment scheme was also instrumental to overcome international fragmentation: EU researchers gained access to key expertise in the U.S. Japan, and Brazil, and conversely allowed our international collaborators to carry out their research in Europe.
Synopsis of major results. A major result has been that the close working together in the participating ten countries (www.sarcosi.org) has established a platform for international research projects and exchanges that this now continued beyond SarcoSi with many bilateral projects in place. Thus, SarcoSi has become a permanent platform for joint international research projects.
Research synergisms. A typical example where progress could be made faster than working in individual teams alone has been the rapid progress on nemaline myopathy during 2012-2016. During this research period, the Beggs and Laporte teams in Boston/Harvard and in Strasbourg/ICGMB respectively identified mutations in the nebulin gene that affect the myofibrillar nebulin filament and cause a muscle weakness in patients as disease underlying primary cause. Making use of this information, the Granzier team in Tucson/Arizona established mouse models that mimic the genetic mutations found in human patients. The Ottenheijm and Labeit teams in Amsterdam and Mannheim identified then molecular signatures for biomarkers in these mouse models confirmed their relevance for human nemaline myopathy diagnosis. Importantly, these biomarkers identified in the SarcoSi network do not only monitor muscle disease, but could also be used to monitor experimental therapeutic interventions in mice to test novel drug candidates for the protection of myofibrillar force. This example illustrates how the close working together of patient oriented groups (Dr. Beggs in Boston at Harvard) with mouse molecular biologists (Dr. Granzier in Tucson) with myofibril experts (Dr. Ottenheijm in Amsterdam) allowed significant translational progress within the four years of our joint research.
In addition to the basic science progress, an important socio-economic impact of the SarcoSi project has been the training of scientists in our network to obtain key expertise in myofibril biology and animal disease models. Each of ten participating teams transferred key knowledge to PhD students. A total of 20 PhD theses included data from SarcoSi supported modules. In three cases, participating young investigators established their own research groups after returning to their home countries. This established key expertise in these countries including research on animal model mimicking human disease, and for research on novel treatment options.
Taken together, defects in myofibril function, both with regards to force production and elasticity are becoming increasingly clinically relevant in our ageing populations. In the past, clinical research on pathological muscle restructuring and wasting is carried out in many different disciplines, including cardiology, pulmonology (for research on diaphragm dysfunctions), sports medicine (for sarcopenia prevention), pediatrics and neurology (for research on neuromuscular hereditary diseases), and gerontology (for addressing remobilization before hospital discharge).
SarcoSi was developed on this background as an innovative research concept to address research fragmentation in our field by putting the sarcomere on the center stage as our common research objective: In SarcoSi, complementary research teams with interdisciplinary expertise have carried out research how in skeletal and cardiac muscle disease settings sarcomeres are affected mechanistically. Our underlying hypothesis in the beginning of the project has been that the sarcomere itself both provides and receives clues from activity and disease states to regulate in turn its status in an autonomous fashion. Finally, we speculated that in turn, sarcomeres provide back signals to the organs to control muscle trophicity (thus the acronym “SarcoSi” for “sarcomeric signaling”).
To achieve our innovative research objectives in SarcoSi in a fast and cost-effective manner, we established a consortium that brought together complementary expertise on an international level. Our vision has been that network expertise should cover the complete range of complexities from the single sarcomere to the patient whose sarcomeric functions are impaired. Therefore in SarcoSi, clinically oriented groups performing studies on patients that have primary defects in their myofibrils (Harvard university) teamed up with groups working on animal disease models for muscle weakness, as well as with basic scientists that focus on single myofibrils to dissect function and structure. Technically, to pave the way to knowledge transfer and innovation within this multidisciplinary setting, research secondments were implemented to bring together the complementary expertise where needed for innovation. Importantly, this secondment scheme was also instrumental to overcome international fragmentation: EU researchers gained access to key expertise in the U.S. Japan, and Brazil, and conversely allowed our international collaborators to carry out their research in Europe.
Synopsis of major results. A major result has been that the close working together in the participating ten countries (www.sarcosi.org) has established a platform for international research projects and exchanges that this now continued beyond SarcoSi with many bilateral projects in place. Thus, SarcoSi has become a permanent platform for joint international research projects.
Research synergisms. A typical example where progress could be made faster than working in individual teams alone has been the rapid progress on nemaline myopathy during 2012-2016. During this research period, the Beggs and Laporte teams in Boston/Harvard and in Strasbourg/ICGMB respectively identified mutations in the nebulin gene that affect the myofibrillar nebulin filament and cause a muscle weakness in patients as disease underlying primary cause. Making use of this information, the Granzier team in Tucson/Arizona established mouse models that mimic the genetic mutations found in human patients. The Ottenheijm and Labeit teams in Amsterdam and Mannheim identified then molecular signatures for biomarkers in these mouse models confirmed their relevance for human nemaline myopathy diagnosis. Importantly, these biomarkers identified in the SarcoSi network do not only monitor muscle disease, but could also be used to monitor experimental therapeutic interventions in mice to test novel drug candidates for the protection of myofibrillar force. This example illustrates how the close working together of patient oriented groups (Dr. Beggs in Boston at Harvard) with mouse molecular biologists (Dr. Granzier in Tucson) with myofibril experts (Dr. Ottenheijm in Amsterdam) allowed significant translational progress within the four years of our joint research.
In addition to the basic science progress, an important socio-economic impact of the SarcoSi project has been the training of scientists in our network to obtain key expertise in myofibril biology and animal disease models. Each of ten participating teams transferred key knowledge to PhD students. A total of 20 PhD theses included data from SarcoSi supported modules. In three cases, participating young investigators established their own research groups after returning to their home countries. This established key expertise in these countries including research on animal model mimicking human disease, and for research on novel treatment options.