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Muscle Stress Relief: An integrated research program linking together basic research on secondary myopathies in stress states to innovative translation in applied myology.

Periodic Reporting for period 2 - Muscle stress relief (Muscle Stress Relief: An integrated research program linking together basic research on secondary myopathies in stress states to innovative translation in applied myology.)

Reporting period: 2018-03-01 to 2020-02-29

Secondary muscle pathologies induced by chronic stress or diseases in other organ systems are becoming endemic in Europe and the rest of the world. A variety of stress signals put striated muscles at risk by impairing their quality and contractile function. Understanding the underlying mechanisms and early recognition of such processes is clinically important because once in place, muscle inactivity many further aggravate the muscle quality in an ongoing vicious cycle of inactivity and muscle wasting. Such pathological events increase the occurrence of metabolic disease and of falls, resulting in high socioeconomic costs and reduced quality of life for millions of sufferers.

MUSCLE STRESS RELIEF aims to improve understanding on how disease mechanisms impact on muscle quality (quantity and functionality), to develop innovation in detection methods for the early diagnosis & efficacious monitoring of muscle stress, and to set the basis towards making them commercially available. The diagnostic approaches and expertise generated by MUSCLE STRESS RELIEF will also provide possibilities to monitor therapeutic strategies, i.e. how muscle can be relieved from stress activation.

An additional aim of MUSCLE STRESS RELIEF is to train the next generation of early-stage researchers (ESRs) as well as help experienced researchers (ERs) to update their skills and forge relationships with innovation actors. Together, the nine academic and five SME beneficiaries, with the four TC academic partners run an integrated intersectoral & international research program, tailored to achieve capacity building and innovation in the field of muscle research and development.
MUSCLE STRESS RELIEF contains seven (7) work-packages (WP), of which six (6) implement the scientific objectives, including research training of ESRs, while one (1) supports the research administration and consortium-wide research networking activities.

Experimental work took place both in Y1 and Y2 of the action and key experimental deliverables were achieved providing new evidence on mechanisms of stress factors interaction on muscle development, regeneration and contractility of skeletal muscles, including identification of targets for subsequent therapeutic interventions. Moreover great progress on identifying biomarkers and improving diagnostic tools has been achieved paving the way for innovation.

Summary of Consortium Achievements
The consortium, among other achievements, has:
• Established and operated the ‘Muscle Stress Relief network office’ and created and used the project’s logo and website
• Identified key genes within the injury-repair context which code for enzymes whose depletion leads to an inadequate muscle regeneration and are working to determine in vivo targeting patterns of those key genes
• Identified critical auto-phagosome activators brought about by mitochondrial dysfunction as well as determined key signalling and denervation mechanisms that lead to muscle wasting.
• Revealed molecular mechanisms underpinning skeletal muscle function under fatigue conditions and showed that renal disease induces appreciable skeletal muscle force depletions at the cellular level.
• Determined pathophysiological mechanisms underlying diaphragm weakening during mechanical ventilation.
• Achieved an advantageous method for the more accurate serological diagnosis of Myasthenia Gravis incl. a novel serological marker for cardiac injury.
• Screened small molecules with a potential to interfere with the identified key genes within the injury-repair context & identified those interfering with muscle stress sensing
• Characterised the role of a novel protein involved with the polarised fusion of muscle myoblasts and ultimately the formation of new muscle fibres
• Defined critical interaction domains in stress signalling in order to develop small molecules or other interference
• Identified novel regulators of autophagy that control muscle mass
• Revealed a strong involvement of oxidative stress in cardiovascular and striated tissue dysfunction
• identified a novel regulatory mechanism of titin-based passive tension, and set the stage to further test diaphragm rescue strategies
• Provided the first evidence that exercise doesn’t worsen myocardial stunning and showed exercise improving cardiovascular function in renal patients.
• Revealed a previously uncharacterized gene that controls longevity and proteostasis
• Identified AAV gene transfers interfering with muscle stress sensing and potential targets to prevent heart failure.
• Developed a very sensitive radioimmunoassay (RIA) for anti-titin antibodies and achieved its simplification for future routine use at the point of care.
• Optimised technology and methodology to characterise stress environments in disease states
• Provided support for improved SME marketing of antibodies diagnostic for muscle stress
• Delivered workshops and training events to ESR and ER in cutting-edge experimental myology methodologies and fostered networking within both academia and industry.
• Provided opportunities to ESRs to strengthen their career potential and supported their next career steps through mentoring and competencies training

In period 1 MUSCLE STRESS RELIEF researchers published > 8 peer-reviewed articles reporting progress in scientific objectives, and provided 5 workshops and 2 seminars to ERs and ESRs as well as dissemination (to the scientific community) and communication (to health professionals and the public) actions.
In period 2 a further 16 peer-reviewed articles were published and more work submitted, with achievement of scientific objectives. Additional workshops and seminars were provided, as well as dissemination and communication actions with a culmination in the final consortium conference in November 22-23, 2019, University of Thessaly. The conference theme was ‘The effect of chronic conditions on muscle biology and function’.
Already MUSCLE STRESS RELIEF has attracted the attention of professional stakeholders and the public. This is because muscle dysfunction is experienced by an increasing percentage of population, linked not only to increases in the lifespan of healthy individuals or patients but most importantly due to the increased prevalence of non-communicable conditions that directly or indirectly affect muscle quality leading to falls and further aggravation of metabolic or inflammatory diseases.

Expected Impact: We expect an improvement in health care by the early detection of biomarkers and improved monitoring. Moreover, we expect Europe’s Research and Innovation potential to benefit from this network by developing research results translated into IP generation & products within the participating five SMEs.

The consortium, through its public website and the participation of its members in both scientific dissemination (including conference presentations, and original articles, as well as consortium led- seminars and workshops) and public communication activities (including social media, TV interviews and public talks or professional outreach) works to communicate findings to scientists and non-scientists alike and attract the younger generation of researchers and health practitioners in the muscle field.

Academic teams and SMEs teams of the MUSCLE STRESS RELIEF consortium, continue in their collaborative efforts to ultimately reduce morbidity and mortality of patients.