Building Muscle Strength

Clinical & societal problem: Inherited cardiac and skeletal muscle diseases pose an enormous economic and social burden on our society. Affected individuals often suffer from disability at young age, leading to loss of healthy years, quality of life, inability to go to a regular school and work, and reliance on family, burden of the caregivers and additional resource use in health and social care. As a result, health and social care expenses are high and societal participation of patients and caregivers is reduced. Based on its genetic nature, inherited cardiac and skeletal muscle diseases affect entire families that live with major concerns about pregnancy, insecurity about disease onset and progression in family members carrying a gene variant (mutation), and the risk of acute cardiac arrest or respiratory failure. Since the number of newly identified mutation carriers is rising, and since therapies for progressive muscle diseases are generally not available, there is an urgent need to: 1) better predict who is at risk to develop severe disease, and 2) design (cost-)effective and personalized therapies to prevent and reverse muscle diseases.

Overall aim: Design and validate human disease models

The Building Muscle Strength (BMS) working group will organize interactive meetings to build a research infrastructure in which knowledge and expertise is shared on human disease models. The BMS working group will unite the national expertise on inherited muscle disease embedded within the Dutch CardioVascular Alliance (DCVA) and the Dutch Muscle Diseases Center (Spierziekten Centrum Nederland, SCN), and thereby unites cardiac and skeletal muscle researchers who share mutual interest in the design of well-validated and high-throughput human disease models. To establish a broad platform, meetings will be multidisciplinary and not only involve researchers with expertise in cell biology, physiology and engineering, but also clinicians, patient organizations and policy makers to increase awareness for available models (state-of-the-art), and identify the need for specific models based on clinical patient experience (progress beyond state-of-the-art).

Precision Medicine for Inherited Muscle Disease

As muscle disorders are caused by a genetic defect, and much progress is made in gene(tic) therapy development, the likelihood of developing novel (preventive and curative) therapeutics in the coming 10 years is high. Inherited muscle diseases have the unique characteristic that the gene defect is identified at young age, which allows timely application of preventive and curative therapies. Using state-of-the-art human muscle systems, we are able to define the changes in muscle properties (function, metabolism) caused by the gene defect, and test mutation-specific efficacy of treatments needed to develop patient-specific treatment strategies. Knowledge exchange between areas of cardiac and skeletal muscle disease will advance both, e.g. through sharing expertise on drug

repurposing, building human stem cell-derived muscle systems, and genetic, biochemical, imaging and mathematical tools.

This network will provide the setting for successful additional (inter)national funding and collaborations and tangible new diagnostics and therapies.