Projects / Programmes
New technology of skeletal muscle atrophy prevention and treatment
| Code |
Science |
Field |
Subfield |
| 3.06.00 |
Medical sciences |
Cardiovascular system |
|
| Code |
Science |
Field |
| B000 |
Biomedical sciences |
|
| Code |
Science |
Field |
| 3.02 |
Medical and Health Sciences |
Clinical medicine |
knee injury, arthroscopic knee surgery, muscle atrophy, ischemic exercise
Researchers (21)
Organisations (4)
Abstract
The decreased stability of injured tissues after joint surgery or injury requires prolonged unloading of joint structures, which also causes substantial muscle atrophy. The degree of quadriceps femoris muscle atrophy is recognized as one of the key factors of poor functional patient outcome. Besides unloading and pain, development of muscle atrophy after surgery is further accelerated by long-term tissue hypoxia induced by surgical procedure and subsequent reperfusion injury. Research on animals shows that reperfusion injury of skeletal muscle can be significantly decreased by previous adaptations of the tissues to ischemia (ischemic preconditioning). However, its effect has not yet been studied in humans. There is however evidence, that exercising at low loads with reduced blood flow through the muscle by inflatable cuff (ischemic exercise) results in same amount of muscle hypertrophy as gained by regular heavy-load exercise. It also appears that post-operative muscle atrophy can be reduced by ~ 50% by application of intermittent muscle ischemia during rest. Therefore we hypothesize that short term pre-operative preconditioning of quadriceps f. muscle with ischemic exercise in combination with application of intermittent ischemia at rest post-operatively, can markedly decrease development of muscle atrophy and muscle weakness. This will be the first randomized controlled clinical trial on the effects of ischemic preconditioning in humans.
The device for optimal performance of ischemic exercise is not yet available on a market. Drawbacks of currently available device are narrow cuffs inducing pressure concentration on small tissue surface, which causes shear forces and significant discomfort. As we recently demonstrated, high cuff pressure during exercise decreases muscle hypertrophy at the site of compression. Other devices utilizing wider cuffs were designed for application on resting tissue (surgery) hence do not assure comfortable and controlled reduction of blood flow during muscle contractions.
Our project consists of two phases. In Prototype phase a prototype of new cuffing system will be developed. New technology will allow the required blood flow reduction in thigh muscles at approx. 40% lower cuff pressure, and simultaneously optimize the regulation of blood flow during contractions. Performance of the prototype will be physiologically evaluated on a group of healthy volunteers. In the subsequent Intervention phase, effectiveness of our ischemic preconditioning protocol will be evaluated on three randomized groups of volunteers elected for unilateral arthroscopic knee surgery. Tests will be carried out before and after pre-operative preconditioning, 14 days after operation and again at 3 and 6 months follow-up. Tests will comprise measurements of muscle cross-sectional areas by MRI, muscle performance tests and functional tests for the lower limb. Simultaneously, partner research group from Norwegian School of Sport Sciences in Oslo, will conduct randomized controlled trial on healthy volunteers in Norway, to elucidate biochemical and morphologic adaptations of muscle cells to the same protocol of ischemic exercise preconditioning.
Given that injuries to the knee are the most frequent injuries in EU and other western countries, poor functional outcome of such patients has a substantial negative economic and social impact. It increases absenteeism, decreases work efficiency and capacity of maintaining proper physical fitness. The new method of muscle atrophy prevention will contribute to decreased costs of postoperative medical care, increased functional ability and higher patient quality of life. Although the device will be developed on a knee-muscle model, minor adaptations will make it easily applicable to other upper and lower limb muscles. Therefore, we estimate that the new product will have a high commercial potential on EU and other global markets.
Significance for science
This is the first research project on a global scale that systematically investigates clinical efficiency of ischemic training. A number of valuable and original scientific information on efficiency and application techniques of ischemic exercise in subjects with knee joint injury or surgery has been obtained. The results of our first clinical study show that preconditioning with short-term ischemic training cannot attenuate atrophy and weakening of Quadriceps Femoris muscle after arthroscopis ACL reconstruction. The results of the second clinical research show that a 3-week low-load ischemic training is more effective than regular resistance training of equal intensity in increasing gains in mass and isokinetic capacity, especially endurance, of both flexor and extensor muscles of the knee. These findings are corroborated with upregulation of mRNA VEGF-A and 3´-aHIF (HIF1A-AS2) and concomitant downregulation of mRNA miostatin (MSTN) and activin receptor (ACVRB2), which however do not appear uniformly in the two muscle groups. These are the first available evidence that tissue hypoxia playing the major role in triggering positive adaptation of atrophied and weakened muscles to ischemic exercise training. A tendency for enhanced effect of ischemic training on the extensor muscle group has been also identified. Given that the extensor muscles are the most affected by knee joint injury, these findings are very promising from a physiotherapy perspective. In contrast, the preliminary results of 6-week ischemic training of knee extensor muscles of healthy subjects performed at ~100 mmHg cuff pressure showed lack of any muscle fibre hypertrophy, satellite cell activation, nuclear addition or increase in capillary density. The lack of effect can be attributed to subthreshold ischemic stimulus and low overall volume of exercise. In conclusion, an optimal dose of ischemic training is required to trigger an augmented positive adaptation of skeletal muscle. This needs to be scrutinized in future experiments.
Significance for the country
The key outcome of the present project is the creation of new scientific knowledge and its direct practical implementation in a form of innovative device for muscle conditioning with restricted blood flow Ischemic Trainer®. The results have contributed to raising the technological level and competitiveness of the only Slovenian company that develops and manufactures medical equipment for physical therapy. An important outcome of the project is also the overall development of the Laboratory of Physiotherapy at Faculty of Health Sciences UL and thereby development of a new scientific field of non-pharmacological therapy of muscular atrophy and weakness in Slovenia, which puts us alongside other European countries with a longer tradition and research capacity in this field. The project has also contributed to the rise in quality of higher education at all levels of study and hence development of the physiotherapy profession in Slovenia. Excellent and very fruitful collaboration with the Orthopaedic Clinic Laboratory and Clinical Institute of Radiology UKC LJ and the Institute of Pathophysiology at the Medical Faculty UL, which was established during the course of the project, continues even after its completion. The research area of the project has been recognized as very topical and as such included in the ARRS research program Molecular mechanisms of development and functioning of skeletal muscle (P3-0043). All in all, the outcomes of the project have gradually increased the overall quality of research in Slovenia and enabled straightforward integration of basic and clinical scientific knowledge for the good of Slovenian patients with musculoskeletal injuries or impairments.
Most important scientific results
Annual report
2013,
2014,
2015,
final report
Most important socioeconomically and culturally relevant results
Annual report
2014,
2015,
final report
