Sparing of muscle mass and function by passive loading in an experimental intensive care unit model

Abstract

Key points• Early physical mobilization of mechanically ventilated intensive care unit (ICU) patients can reduce the length of stay in the ICU and hospital and improve muscle strength and functional outcomes.• A unique experimental rat ICU model has been used to study the effects and underlying mechanisms of unilateral passive mechanical loading on skeletal muscle size and function at durations varying between 6 h and 2 weeks.• Passive mechanical loading attenuated the loss of muscle mass and force-generation capacity associated with the ICU intervention.• The maintained muscle mass and function by passive loading is probably due to lower oxidative stress and a reduced loss of the molecular motor protein myosin.• The beneficial effects of passive mechanical loading on muscle size and function strongly support the importance of early and intense physical therapy in immobilized ICU patients.Abstract The response to mechanical stimuli, i.e. tensegrity, plays an important role in regulating cell physiological and pathophysiological function, and the mechanical silencing observed in intensive care unit (ICU) patients leads to a severe and specific muscle wasting condition. This study aims to unravel the underlying mechanisms and the effects of passive mechanical loading on skeletal muscle mass and function at the gene, protein and cellular levels. A unique experimental rat ICU model has been used allowing long-term (weeks) time-resolved analyses of the effects of standardized unilateral passive mechanical loading on skeletal muscle size and function and underlying mechanisms. Results show that passive mechanical loading alleviated the muscle wasting and the loss of force-generation associated with the ICU intervention, resulting in a doubling of the functional capacity of the loaded versus the unloaded muscles after a 2-week ICU intervention. We demonstrate that the improved maintenance of muscle mass and function is probably a consequence of a reduced oxidative stress revealed by lower levels of carbonylated proteins, and a reduced loss of the molecular motor protein myosin. A complex temporal gene expression pattern, delineated by microarray analysis, was observed with loading-induced changes in transcript levels of sarcomeric proteins, muscle developmental processes, stress response, extracellular matrix/cell adhesion proteins and metabolism. Thus, the results from this study show that passive mechanical loading alleviates the severe negative consequences on muscle size * G. Renaud and M. Llano-Diez contributed equally to this paper

The Sick and the Weak: Neuropathies/Myopathies in the Critically Ill

“…In an experimental study using a novel rat ICU model where animals were exposed to neuromuscular blockade and mechanical ventilation for durations varying from Ͻ1 day to 14 days, it was confirmed that unilateral loading 12 h/day had a positive effect on skeletal muscle structure and function (574). That is, both the loss of muscle fiber size and specific force at the single muscle fiber level were significantly attenuated in response to passive loading, resulting in a doubling of the functional capacity on the loaded versus the unloaded side (574).…”

“…In an experimental study using a novel rat ICU model where animals were exposed to neuromuscular blockade and mechanical ventilation for durations varying from Ͻ1 day to 14 days, it was confirmed that unilateral loading 12 h/day had a positive effect on skeletal muscle structure and function (574). That is, both the loss of muscle fiber size and specific force at the single muscle fiber level were significantly attenuated in response to passive loading, resulting in a doubling of the functional capacity on the loaded versus the unloaded side (574). The mechanisms underlying the loading effects showed a complex temporal pattern involving oxidative stress, posttranslational protein modifications, transcriptional regulation of myosin synthesis, protein degradation via the E3 ligase MuRF1, and extracellular matrix/cell adhesion proteins (574).…”

“…Tensegrity or "tensional integrity," a term derived from architecture, describes the interaction between isolated components within a system under mechanical compression or tension and resulting structure. It has been introduced to muscle biology to summarize cellular functional and structural responses to mechanical stimuli (574). For example, mechanical signals may induce increased protein synthesis, satellite cell activation, and release of growth factors and may overlap with metabolic, action potential-induced, and oxidative signaling (576).…”

“…That is, both the loss of muscle fiber size and specific force at the single muscle fiber level were significantly attenuated in response to passive loading, resulting in a doubling of the functional capacity on the loaded versus the unloaded side (574). The mechanisms underlying the loading effects showed a complex temporal pattern involving oxidative stress, posttranslational protein modifications, transcriptional regulation of myosin synthesis, protein degradation via the E3 ligase MuRF1, and extracellular matrix/cell adhesion proteins (574). Similar effects were observed in both fast-and slow-twitch limb muscles, but the effects of loading were typically more pronounced in slow-versus fasttwitch muscles.…”

“…However, all ICU patients with CIM have exposure to long-term mechanical ventilation and immobilization in common. Furthermore, the complete "mechanical silencing," unique for ICU patients, has been shown to play an important role in the development of CIM in experimental and clinical studies (435,517,574). An additional factor that needs to be taken into account is the relatively long delay between exposure to trigger factors and the phenotype characterizing CIM, i.e., severe muscle wasting and preferential myosin loss (399,511,610).…”