Gautel, Mathias

The muscle wasting and impaired muscle function associated with critical llness in ICU patients have negative consequences for recovery from primary disease, but are also the most persistent and debilitating of problems for ICU survivors years after hospital discharge. This study aims at improving our understanding of the mechanisms underlying the muscle wasting in ICU patients by conducting time‐resolved analyses of skeletal muscle structure and function together with measurements of protein synthesis rate, myofibrillar protein and gene expression and intracellular signaling in response to post‐synaptic block of neuromuscular transmission (NMB), sedation, mechanical ventilation and muscle unloading at durations varying from hours to two wks by using a unique experimental rat ICU model. Skeletal muscle structure and function were well maintained during the first four days, followed by a dramatic and progressive decline in muscle size and function. The preferential loss of the molecular motor protein myosin and impaired forcegenerating capacity (specif force) are the major causes underlying the impaired skeletal muscle function in the ICU model. Muscle unloading due to lack of weightbearing (external unloading) and muscle membrane depolarization (internal unloading) are forwarded as very important underlying factors. Supported by the Sweish Research Council and AFM

Single-molecule atomic force microscopy (AFM) was used to investigate the mechanical properties of titin, the giant sarcomeric protein of striated muscle. Individual titin molecules were repeatedly stretched, and the applied force was recorded as a function of the elongation. At large extensions, the restoring force exhibited a sawtoothlike pattern, with a periodicity that varied between 25 and 28 nanometers. Measurements of recombinant titin immunoglobulin segments of two different lengths exhibited the same pattern and allowed attribution of the discontinuities to the unfolding of individual immunoglobulin domains. The forces required to unfold individual domains ranged from 150 to 300 piconewtons and depended on the pulling speed. Upon relaxation, refolding of immunoglobulin domains was observed.