Molecular Mechanisms Underlying Intensive Care Unit-Acquired Weakness and Sarcopenia

Marcela Kanova, Pavel Kohout, Marcela Kanova, Pavel Kohout

Abstract

Skeletal muscle is a highly adaptable organ, and its amount declines under catabolic conditions such as critical illness. Aging is accompanied by a gradual loss of muscle, especially when physical activity decreases. Intensive care unit-acquired weakness is a common and highly serious neuromuscular complication in critically ill patients. It is a consequence of critical illness and is characterized by a systemic inflammatory response, leading to metabolic stress, that causes the development of multiple organ dysfunction. Muscle dysfunction is an important component of this syndrome, and the degree of catabolism corresponds to the severity of the condition. The population of critically ill is aging; thus, we face another negative effect-sarcopenia-the age-related decline of skeletal muscle mass and function. Low-grade inflammation gradually accumulates over time, inhibits proteosynthesis, worsens anabolic resistance, and increases insulin resistance. The cumulative consequence is a gradual decline in muscle recovery and muscle mass. The clinical manifestation for both of the above conditions is skeletal muscle weakness, with macromolecular damage, and a common mechanism-mitochondrial dysfunction. In this review, we compare the molecular mechanisms underlying the two types of muscle atrophy, and address questions regarding possible shared molecular mechanisms, and whether critical illness accelerates the aging process.

Keywords: intensive care unit-acquired weakness; muscle atrophy; proteostasis; rapamycin system; sarcopenia; ubiquitin–proteasome system.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Protein turnover in the young, the old, and the critically ill partly according to [11]: In old patients, protein synthesis decreases postprandially due to anabolic resistance; compared to young patients, the protein balance becomes negative over time, leading to sarcopenia. Proteolysis between meals postabsorptively does not change significantly. In critically ill patients, on the one hand, proteosynthesis is affected due to anabolic resistance, but above all, proteolysis is markedly activated, for the need of protein as source of stress metabolism-activated gluconeogenesis. Protein balance is strongly negative; ICUAW develops rapidly.
Figure 2
Figure 2
Signaling pathways that activate caspase3 and the UPS in skeletal muscle. Schematic of the main molecular pathways balancing muscle protein synthesis and proteolysis. Sepsis, inflammation, and immobility shift this balance towards protein breakdown. X means insulin resistance, block of insulin receptor.
Figure 3
Figure 3
Signaling pathway of muscle protein synthesis. Insulin and insulin-like growth factors (IGF) act through phosphoinositol-3-kinase (PI3K) and Akt kinase to activate mammalian target of rapamycin (raptor mTORC1 and rictor mTORC2). Adequate supply of amino acids (leucine) in the diet activates Rag GTPase and activates raptor mTORC1, but not rictor mTORC2.
Figure 4
Figure 4
Mitochondrial biogenesis according to [32]. The central regulator of mitochondrial biogenesis: peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Transcription factors (TFs): forkhead box class-O (FoxO1), hepatocyte nuclear factor 4a (HNF4a), nuclear respiratory factor (NRF1, NRF2).
Figure 5
Figure 5
Mitochondrial dynamics (fission and fusion events) according to [37]. The central regulator of mitochondrial biogenesis: peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α). Transcription factors (TFs): forkhead box class-O (FoxO1), hepatocyte nuclear factor 4a (HNF4a), nuclear respiratory factor (NRF1, NRF2).
Figure 6
Figure 6
Mitophagy (schematic representation of the autophagy machinery) partly according to [32].
Figure 7
Figure 7
Exercise-induced muscle growth through induced proteolysis and induced autophagy according to [59]. Exercise-induced protein damage via increased ROS/mechanical and heat stress, increased MuRF1, and atrogin-1 (MAFbx), and both muscle-specific ubiquitin ligases lead to the activation of the 26 S proteasome to rid the cells of non-functional myofibrillar proteins. Exercise also activates autophagy: beclin-1 is phosphorylated and released from the BCL2–beclin-1 complex. Exercise-induced autophagy is necessary for the clearance of damaged organelles and proteins. This is critical for skeletal muscle remodeling and growth.

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