Projects / Programmes
Molecular mechanisms of skeletal muscle atrophy: Implications in age, muscle disease and space habitation.
Code |
Science |
Field |
Subfield |
3.06.00 |
Medical sciences |
Cardiovascular system |
|
Code |
Science |
Field |
B580 |
Biomedical sciences |
Skeleton, muscle system, rheumatology locomotion |
Code |
Science |
Field |
3.02 |
Medical and Health Sciences |
Clinical medicine |
skeletal muscle, muscle atrophy, microRNA, master regulators
Researchers (1)
no. |
Code |
Name and surname |
Research area |
Role |
Period |
No. of publicationsNo. of publications |
1. |
30697 |
PhD Anja Kovanda |
Neurobiology |
Head |
2014 - 2017 |
75 |
Organisations (1)
no. |
Code |
Research organisation |
City |
Registration number |
No. of publicationsNo. of publications |
1. |
0106 |
Jožef Stefan Institute |
Ljubljana |
5051606000 |
90,361 |
Abstract
Skeletal muscle atrophy and the associated loss of mobility are growing public health and economic concerns. In healthy individuals, muscle atrophy is induced by inactivity, aging, nutrient restriction or, in case of astronauts, microgravity during space habitation. Severe, progressive and often fatal muscle atrophy is also caused by some primary muscular and neuromuscular disorders such as myotonic dystrophy and amyotrophic lateral sclerosis. Additionally, muscle atrophy is both induced by and exacerbates many chronic and infectious diseases, such as cancer (cachexia), multiple sclerosis, AIDS, COPD, CKD, and diabetes. Therefore muscle atrophy prevention is an important therapeutic goal.
Transcriptomic changes play a key role in the development of atrophy, where they were shown to affect pathways such as TGF-beta, NF-kB, apoptosis, cell-cycle arrest, membrane trafficking/cytoskeleton organization, inflammation, insulin resistance etc. Muscle atrophy caused by primary or secondary muscle disorders involves both general and disease-specific molecular pathways. The complexity of changes during atrophy highlights the need for a better understanding of underlying transcriptional processes and for identification of ‘master regulator’ targets for intervention. Traditional comparison of diseased patients(with atrophy) and matched healthy controls(without atrophy) doesn’t enable us to determine disease-specific factors as because atrophy is a complex process affecting expression of thousands of genes. Therefore comparison of patients with general atrophy controls is needed. The sustained bed rest model of healthy subjects, which is a part of the Planetary Habitat Simulation Study, funded by EU FP7, offers a unique opportunity to study both general and cause-specific mechanisms of muscle atrophy, by providing a background to which disease-induced atrophy can be compared.
microRNA (miRNA) are short non-coding RNAs that are important in fine-tuning the expression of majority of genes, and by preventing translation of target mRNAs, can serve as master regulators in the development of atrophy. In animal and cell models, some of the identified muscle-specific miRNAs or myomirs have already shown potential as targets of therapeutic intervention in ameliorating muscle atrophy. Because of species-specific molecular differences animal research cannot be directly translated to humans. A precise characterization of cause-specific 'master regulators' needs to be performed in order to identify suitable therapeutic targets in humans.
In our recent pilot study we were the first to examine global expression of miRNAs in skeletal muscle after 10 day bed rest in healthy males and showed that miRNAs may govern regulatory processes involved in muscle atrophy.
The aim of the postdoctoral project is both to find parallels and differentiate between master regulators in general and disease-specific atrophy in order to increase the understanding of the process as well as to develop ways of delaying or preventing atrophy. Specifically, we aim to (1) identify global and disease-specific miRNAs in muscle tissue; (2) to identify general and disease-specific pathways that could be targeted in muscle atrophy prevention in aging, disease or space exploration. Finally, (3) in case we identify novel miRNAs, we will design suitable quantitative PCR assays.
We expect to identify miRNA master-regulators of general-, disease- and age-associated muscle atrophy. There is a strong rationale for examining miRNAs as therapeutic targets, as local application of muscle specific miRNAs has already been shown to improve regeneration in several tissue and animal models of muscle atrophy.
The project will enable us to characterize, in depth, global-, disease- and age-associated miRNA changes in muscle tissue; and to identify both master-regulators, that can be used for treatment of muscle atrophy, and biomarkers that will facilitate causative diagnosis in diseases causing muscle atr
Significance for science
Skeletal muscle atrophy and the consequent loss of mobility represent growing public-health and economic problems. In developed countries especially, the increasingly sedentary population is aging and inactivity affects an increasing proportion of the population, both patients as well as their care-takers. Primary muscular and neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), cause a relentlessly progressive and often lethal muscular atrophy and currently there is no therapy for most of these diseases. Additionally, muscle atrophy can be caused by many chronic and infective diseases, such as cancer (cachexia), multiple sclerosis, AIDS, obstructive pulmonary disease, chonic kidney disease and diabetes. In these cases, muscle atrophy both follows and exacerbates the primary disease. Therefore, preventing or improving muscle atrophy represents an important therapeutical challenge. The main goal of our postdoctoral project was to characterize the changes in expression of miRNA, which act as main regulators in the development of muscle atrophy. Studies performed so far on muscle atrophy have been focused primarily on the coding transcriptome and have left out miRNAs. However, miRNAs actually determine whether the expressed mRNAs will ultimately be translated into proteins. So far the studies on animal and cellular models have shown some myomirs (muscle miRNAs) to be good targets for treatment and prevention of muscle atrophy. However, due to species-specific molecular differences the results from animal studies cannot directly be translated into human research. Our project offers the first basic characterization of the main regulators of muscle atrophy in humans, which is paramount for determining actual therapeutic targets. In the postdoctoral project, which represents the first study of its’ kind including the global miRNA and small RNA expression comparison of still-active muscle tissue of ALS patients and healthy, age-matched controls, we have gathered information on the changes of the main regulators in muscle atrophy. Additionally, the study has enabled us to evaluate the human-specific regulatory pathways connected with miRNA in muscle atrophy, which forms a stepping stone for further work in this field. The characterization of disease-specific miRNAs offers additional opportunities to develop novel therapeutic approaches for prevention, slowing and treatment of muscle atrophy in ALS. All data collected during the study has been deposited in a publicly available database Gene Expression Omnibus (GEO Series accession number GSE100188), as well as published in an open-access journal Scientific reports [1] and presented at several national and international symposia. We hope this will encourage exchange of information with other scientists as well as enable further research in this field. [1] KOVANDA, Anja, LEONARDIS, Lea, ZIDAR, Janez, KORITNIK, Blaž, DOLENC-GROSELJ, Lea, RISTIĆ-KOVAČIČ Stanka, CURK, Tomaž, ROGELJ, Boris. Differential expression of microRNAs and other small RNAs in muscle tissue of patients with ALS and healthy age-matched controls. Scientific reports, ISSN 2045-2322, 2018 Accepted, In press
Significance for the country
Skeletal muscle atrophy and the consequent loss of mobility represent growing public-health and economic problems with the increasing aging of the population. Primary muscular and neuromuscular disorders, including amyotrophic lateral sclerosis (ALS), cause a relentlessly progressive and often lethal muscular atrophy. Currently there is no therapy for most of these diseases, and furthermore, because these are mostly rare diseases, small populations such as the that of Slovenia, remain both under-studied and underrepresented in basic research studies. In the postdoctoral project, which represents the first study of its kind globally, we have, based on the comparison of small RNA molecules (including miRNAs) in still-active muscle tissue of Slovenian patients with ALS and healthy, age-matched controls, collected important information on the changes in the levels of the main regulators involved in muscle atrophy. This has enabled us to determine human-specific regulatory pathways involving miRNAs in muscles undergoing atrophy caused by ALS. This information forms an important first step in further studies in this field. For ALS patients, the characterization of disease-specific miRNAs opens future possibilities for the development of novel therapeutic approaches for the prevention, slowing-down and treatment of atrophy. During our project we have additionally improved collaboration between the groups and disciplines involved in studying muscle atrophy in Slovenia; medical physiology, clinical management, and molecular biology. Information obtained as part of the study has been made available to the public through the Gene Expression Omnibus database (GEO Series accession number GSE100188), as well as published in an open-access journal Scientific Reports [1]. The study represents an important basis for further research of main regulators of muscle atrophy, as it enables the exchange of information comparison of results with other scientists both globally and in the Slovenian research setting. [1] KOVANDA, Anja, LEONARDIS, Lea, ZIDAR, Janez, KORITNIK, Blaž, DOLENC-GROSELJ, Lea, RISTIĆ-KOVAČIČ Stanka, CURK, Tomaž, ROGELJ, Boris. Differential expression of microRNAs and other small RNAs in muscle tissue of patients with ALS and healthy age-matched controls. Scientific reports, ISSN 2045-2322, 2018 Accepted, In press
Most important scientific results
Annual report
2014,
final report
Most important socioeconomically and culturally relevant results
Annual report
2014,
final report