@phdthesis{discovery1425686,
          editor = {HE Montgomery},
            year = {2014},
          school = {UCL (University College London)},
           title = {Acute skeletal muscle wasting in the critically ill},
           pages = {1 -- 197},
           month = {April},
            note = {Unpublished},
             url = {https://discovery.ucl.ac.uk/id/eprint/1425686/},
        abstract = {Introduction: Critical illness survivors demonstrate skeletal muscle wasting with associated functional impairment. I prospectively characterised this process, and defined the pathogenic roles of altered protein synthesis and degradation.

Methods: Critically ill patients (n=63, 59\% male, age 54.7{$\pm$}18.0 years, APACHE II score 23.5{$\pm$}6.5) were recruited {\ensuremath{<}}24 hours following intensive care admission. Muscle loss trajectory was determined through serial ultrasound measurement of rectus femoris cross-sectional area (RFCSA) and, in a subset, quantification of myofibre area (FibreCSA) and protein/DNA ratio. Histopathological analysis
was performed. Muscle protein synthesis and breakdown rates were determined and respective signalling pathways examined.

Results: RFCSA decreased significantly, (-17.7{$\pm$}12.1\%, [p{\ensuremath{<}}0.001]), underestimating muscle loss determined by FibreCSA (-10.3{$\pm$}10.9\% vs.-17.5{$\pm$}30.2\%, p=0.31), or protein/DNA ratio (-10.3{$\pm$}10.9\% vs. -29.5{$\pm$}41.5\%, p=0.03). Fall in RFCSA was greater in multi- than single-organ failure (-21.5{$\pm$}10.5\% vs. - 7.2{$\pm$} 9.7\%, p {\ensuremath{<}}0.0001), even by day 3 (-8.7{$\pm$}16.3\% vs. -1.8{$\pm$} 9.6\%, p{\ensuremath{<}}0.01). Myofibre necrosis occurred in {\ensuremath{>}}50\% (20/37) of subjects. Protein synthesis was depressed to levels observed in fasted controls (0.035{$\pm$}0.018\%/hr vs. 0.039{$\pm$}0.011\%/hr, p=0.57), and increased by day 7 (0.076{$\pm$}0.066\%/hr, p=0.03)
to levels associated with fed controls (0.065+0.018\%/hr, p=0.30,) independent of nutritional load.
Protein breakdown remained elevated throughout (8.5{$\pm$}5.7 to 10.6{$\pm$}5.7mmol phe/min/IBW, p=0.4).Principal component analysis of intracellular signalling supported a programme of increased breakdown (r=-0.83, p=0.005) and depressed synthesis (r=-.69, p=0.041).

Conclusions: Early rapid skeletal muscle wasting occurs in critical illness, is greatest in those with multi-organ failure, and results from suppression of protein synthesis and increases in catabolism. These effects are independent of feeding and are commonly associated with myonecrosis.},
        keywords = {Muscle, Intensive care, protein synthesis, protein homeostasis},
          author = {Puthucheary, ZA}
}