Skeletal Muscle Regeneration in Survivors of Critical Illness: How to Prevent Satellite Cell Failure?

Background:

Muscle weakness is a common complication in patients who survived a serious critical illness or trauma. Altered muscle strength and functional ability significantly worsens the patients' performance and quality of life. Specific treatment does not exist and the pathogenesis is not yet fully understood. Acute sepsis or extensive inflammatory response are the main risk factors for the muscle weakness development in critically ill patients. Recent studies have shown that muscle weakness can be caused by the loss of ability of skeletal muscle cells to react to the injury and regenerate. Skeletal muscle satellite cells, which are localized beneath the basal lamina of individual muscle fibers, are responsible for muscle regeneration. After the muscle damage, satellite cells are activated from quiescent state (G0 phase) and enter the cell cycle (G1 phase). Subsequently, they proliferate and differentiate into the myoblasts which then fuse and form multinucleated cylindrical myotubes. The cells then merge into the myofibrils and join the muscle fibers that were not damaged. Some satellite cells return to the G0 state to replenish the pool of quiescent skeletal muscle cells. In response to satellite cell damage, mitochondrial biogenesis and synthesis of new myofibrillar proteins are activated to build the new muscle mass containing new intracellular content. Thus, satellite cells have a crucial role for muscle fiber regeneration. Pilot studies performed on animal models (e. g. laboratory mice that developed the acute sepsis) demonstrated a reduction in mitochondrial content and DNA, increased production of reactive oxygen species and changes in oxidative phosphorylation. The abnormalities in the bioenergetic profile of satellite cells are considered a cause of their reduced ability to regenerate. However, the exact mechanism has not yet been fully elucidated. Changes in the mitochondrial structure and dynamics of satellite cells in critically ill patients are also unknown. In last years, the association of mitochondrial functions with mitochondrial dynamics has been investigated in various pathological conditions and diseases. Depending on external insults and metabolic demands, mitochondria undergo dramatic shape changes that can have a very significant impact on cellular metabolism. The balanced process of mitochondrial fission and fusion plays a key role in the mitochondrial biogenesis and removal of damaged mitochondria. The process is absolutely necessary for the proper growth and function of the muscle tissue. Mitochondrial dynamics and morphology can be altered under pathological circumstances: under the mild stress and starvation, mitochondrial morphology can change from small spheres or short rods to long tubules with an increased capacity for oxidative phosphorylation. On the other hand, acute severe stress leads to a mitochondrial fission and defective oxidative phosphorylation. Several studies performed on animal models demonstrated that proteins responsible for the process of mitochondrial fusion and fission are absolutely crucial for the proper growth and function of skeletal muscle cells. Therefore, alterations in mitochondrial dynamics often play a crucial role in skeletal muscle dysfunction and have been recently extensively studied in several myopathies.

In this project, the investigators would like to investigate the causal relationships between mitochondrial function and their shape in satellite cells obtained from critically ill patients in the acute, protracted and post-ICU phase of critical illness.

Hypotheses and aims of the project:

In light of this, the investigators hypothesize that critical illness induces damage to satellite cells in skeletal muscle that later impairs skeletal muscle structural and functional recovery and contributes to persistent weakness and failed functional outcome.