Projects / Programmes
Molecular Mechanisms underlying development and function of the skeletal muscle
January 1, 2015
- December 31, 2019
| Code |
Science |
Field |
Subfield |
| 3.03.00 |
Medical sciences |
Neurobiology |
|
| Code |
Science |
Field |
| B007 |
Biomedical sciences |
Medicine (human and vertebrates) |
| Code |
Science |
Field |
| 3.01 |
Medical and Health Sciences |
Basic medicine |
skeletal muscle, sarcopenia, muscle regeneration, cytokines-myokines, neuromuscular diseases, myopathies, critical illness myopathy, ischaemia-reperfusion injury, neurogenic muscle injury, cancer, diagnostic approaches, therapeutic approaches-targets, translational research
Researchers (36)
Organisations (2)
Abstract
Problem identification. Sarcopenia, defined as the loss of skeletal muscle mass and function, is conducive to disability, low quality of life as well as increased morbidity and mortality. Due to the ageing of the population and the physically inactive life style sarcopenic conditions, including ageing-related sarcopenia, cancer and critical illnesses are likely to become one of the most prevalent problems in medicine. The search for therapeutic strategies to improve muscle function has been challenging, and we currently lack effective options for prevention or treatment of muscle wasting. Elucidation of the underlying molecular mechanisms and identification of novel pharmacological approaches therefore remains a major target of current research efforts.
Objectives. The main research objective will be to investigate the mechanisms underlying the loss and recovery of skeletal muscle mass and function. The research programme will be divided into six work packages (WPs), which will address relevant research issues in the context of specific clinical problems associated with skeletal muscle dysfunction. Specifically, we will investigate critical illness myopathy (WP1), ischaemia-reperfusion injury (WP2), nerve injury and neurogenic muscle dysfunction (WP3) as well as cancer-induced muscle wasting (WP4). Each of these constitutes a major clinical problem which may have a long-term and devastating impact on patient health and quality of life. Thus, our efforts will be directed primarily towards the identification of new strategies to prevent or treat skeletal muscle loss and dysfunction in these conditions. In addition, we will explore mechanisms underpinning functional specialization of muscle fibers (WP5), which might be exploited for pharmacological stimulation of protective functional adaptations in skeletal muscle. Finally, we will aim to identify putative undiagnosed cases of Pompe disease in Slovenia to make it possible for them to receive enzyme replacement therapy (WP6).
Impact. Taken together, the proposed studies will up-grade and expand our investigations from the past five years and will provide new insights into the mechanisms underlying structural and functional adaptations in skeletal muscle under physiological and pathological conditions. Collectively, our work may lead to the identification of novel targets that could open new avenues for the development of innovative strategies to prevent or treat skeletal muscle dysfunction. Finally, the educational aspect of the programme is of the outmost importance. Indeed, being the sole research programme in the field, we will continue to provide a platform for translational skeletal muscle research in Slovenia. Also, we will actively seek to expand our research network and to foster new collaborations with experts in the field. Moreover, to promote skeletal muscle research in Slovenia, we will provide opportunities for the education and training of students, young scientists, and clinicians.
Significance for science
The proposed studies will upgrade our investigations from the past five years and will provide new insights into the mechanisms underlying structural and functional adaptations in skeletal muscle under physiological and pathological conditions. Collectively, our work may lead to the identification of novel targets that could open new avenues for the development of innovative strategies to prevent, limit or treat skeletal muscle dysfunction.
WP1: Critical illness myopathy
Despite its devastating impact, CIM has been recognized as a research priority only recently1 and its complex pathogenesis remains unclear. We will determine the role of Na+-K+-ATPase and IL-6 in pathogenesis of CIM. Pharmacological agents targeting Na+-K+-ATPase may counteract loss of sarcolemmal excitability in CIM. In the light of a recently identified link between Na+-K+-ATPase and autophagy2, such agents might also block muscle atrophy. The evaluation of the role played by IL-6 in CIM is also important, because tocilizumab, a humanized anti-IL-6 receptor antibody, is available for clinical use. Finally, we expect to validate the use of the myosin/actin ratio and myofibrillar ATP-ase activity as a diagnostic method in suspected CIM. Taken together, our results will provide further insights into pathogenesis of CIM, which may provide basis for novel therapeutic or diagnostic approaches.
WP2: Prevention and treatment of the ischaemia-reperfusion injury
IRI can prolong postoperative recovery and lead to life-threatening complications. We will determine the mechanisms underpinning IRI in skeletal muscle. Uncovered, these mechanisms may provide new avenues for pharmacological intervention in IRI-induced muscle dysfunction. Such approaches might shorten postoperative recovery and reduce the risk of crush syndrome. In addition, we will improve approaches for the analysis of the capillary net that may overcome current challenges such as artefacts and small samples. Improvements in the two-dimensional quantification may be particularly useful for the assessment of clinical muscle samples, because the amount of tissue is often too low for the application of three-dimensional approaches.
WP3: Muscle-nerve interactions in muscle injury and regeneration
Nerve injury leads to muscle atrophy directly and indirectly via cytokine secretion3. Conversely, pharmacological stabilisation of the neuromuscular junction might prevent muscle atrophy4. We will elucidate whether myotoxicity and neurotoxicity of local anaesthetics could be mitigated by improvements in pharmaceutical formulation or technique of administration. Furthermore, we will determine whether optical projection tomography could be used for assessment of nerve structure. Such approach may overcome current challenges for the structural assessment of nerve injury. Our investigations may provide basis for the development of less toxic anaesthetic formulations and improved techniques of delivery. Finally, we will determine the role of trophic factors such as agrin in the regulation of muscle regeneration. Nerve-muscle cross-talk is a promising target for promotion of muscle regeneration following injury.
WP4: Cancer-related alterations in skeletal muscle
Cancer-induced cachexia not only reduces quality of life, but also leads to poor therapeutic response and adverse clinical outcomes. Conversely, regular exercise exerts beneficial effects on skeletal muscle function and protects against various types of cancer. We will determine how exercise and high-fat diet interact to modulate skeletal muscle oxidative potential and capillary net in colon cancer. Also, we will elucidate molecular mechanisms underlying communication between skeletal muscle and cancer cells via cytokines and secreted miRNAs. Blocking signalling from cancer cells to skeletal muscle may protect against muscle wasting. Conversely, stimulation of exercise-induced signalling pathways emanating from skeletal muscle may exert anti-cancer effects.
Significance for the country
Pathological conditions that affect skeletal muscle are one of the major health problems in the developed world, including Slovenia. Sarcopenia of the elderly strikes practically every ageing individual at least to some extent. The result is impaired mobility, which seriously affects quality of life and increases frequency of traumatic injury. Due to longer life expectancy, muscle pathology might well become the most widespread health problem, and therefore also the greatest socio-economic problem, in the developed world.
This has led to increased scientific interest for an understanding of the function and development of normal muscle and for the pathophysiological basis and consequences of various clinical conditions that affect skeletal muscle. To keep up with increasing knowledge in this field, and to contribute to these scientific efforts, it is of utmost importance for Slovenia to have established scientific groups actively involved in this field. With our contacts with other researchers who are working on this scientific problem, this group has a central role in coordination of research in this field in Slovenia. With the need for multidisciplinary approaches, the role of this group extends also to the coordination of various approaches in muscle research, including basic laboratory and clinical (diagnostics and therapeutic) research, and research aimed at innovations in technological aspects.
It is essential for the scientific development of Slovenia and for its scientific recognition to be integrated into the European and global research communities. One of the main goals of our programme is therefore to actively participate in various aspects of scientific life at an international level. Following our past and ongoing practice, we apply for projects under international calls, publish in high quality international journals, and take part in international symposia, to help in the dissemination of our results. Members of the group are also editors and on editorial boards of international peer-review journals, and reviewers for various EU calls. In this way, we are establishing important bonds to further promote scientific exchanges between Slovenia and other countries.
One of the most important socio-economic goals of our research is higher education. It must be emphasised that our programme has been (see report for previous period of financing), and will continue to be, tightly connected with all levels of educational processes in undergraduate and postgraduate studies in medicine, dental medicine, pharmacy, biochemistry and nursing. Under the mentorship of the scientists of our group, students will prepare scientific theses in the field of skeletal muscle at various levels: e.g., Prešeren’s award, diplomas, and MSc and PhD theses.
It is an established practice in our group to provide our junior investigators with training of about a year in top laboratories in renowned academic institutions abroad, such as with Columbia University and New York University in the USA, the Karolinska Institutet in Sweden, and the Baker Heart Institute in Melbourne, Australia. We will continue with this practice in the future, as we believe that it provides an essential basis for further development of high quality research in Slovenia. The orientation of our group towards promotion of international integration is evident also from our participation in coordination of Erasmus and mobility programmes at the Faculty of Medicine at the University of Ljubljana.
One activity of our group that is particularly important in socio-economic terms is wide dissemination of our results, aimed at increased public participation and social awareness of muscle-related health problems. We continue to participate in education of the general population, which has included video presentations on television, articles in daily newspapers, and other forms to reach wide dissemination. It is our goal to increase the awareness of the importance of preserv
Most important scientific results
Annual report
2015,
interim report,
final report
Most important socioeconomically and culturally relevant results
Annual report
2015,
interim report,
final report
