ICU survivors of greater than or equal to 1 week of MV may be stratified into four disability groups based on age and ICU length of stay. These groups determine 1-year recovery and healthcare use and are independent of admitting diagnosis and illness severity. Clinical trial registered with www.clinicaltrials.gov (NCT 00896220).
Long-term weakness in ICU survivors results from heterogeneous muscle pathophysiology with variable combinations of muscle atrophy and impaired contractile capacity. These findings are not explained by ongoing muscle proteolysis, inflammation, or diminished mitochondrial content. Sustained muscle atrophy is associated with decreased satellite cell content and compromised muscle regrowth, suggesting impaired regenerative capacity.
In this study, most caregivers of critically ill patients reported high levels of depressive symptoms, which commonly persisted up to 1 year and did not decrease in some caregivers. (Funded by the Canadian Institutes of Health Research and others; ClinicalTrials.gov number, NCT00896220.).
Skeletal muscle atrophy in individuals with advanced chronic obstructive pulmonary disease (COPD) is associated with diminished quality of life, increased health resource use, and worsened survival. Muscle wasting results from an imbalance between protein degradation and synthesis, and is enhanced by decreased regenerative repair. We investigated the activation of cellular signaling networks known to mediate muscle atrophy and regulate muscle regenerative capacity in rodent models, in individuals with COPD (FEV(1) < 50% predicted). Nine patients with COPD and nine control individuals were studied. Quadriceps femoris muscle isometric contractile force and cross-sectional area were confirmed to be significantly smaller in the patients with COPD compared with control subjects. The vastus lateralis muscle was biopsied and muscle transcript and/or protein levels of key components of ubiquitin-mediated proteolytic systems (MuRF1, atrogin-1, Nedd4), inflammatory mediators (IkappaBalpha, NF-kappaBp65/p50), AKT network (AKT, GSK3beta, p70S6 kinase), mediators of autophagy (beclin-1, LC3), and myogenesis (myogenin, MyoD, Myf5, myostatin) were determined. Atrogin-1 and Nedd4, two ligases regulating ubiquitin-mediated protein degradation and myostatin, a negative regulator of muscle growth, were significantly increased in the muscle of patients with COPD. MuRF1, Myf5, myogenin, and MyoD were not differentially expressed. There were no differences in the level of phosphorylation of AKT, GSK3beta, p70S6kinase, or IkappaBalpha, activation of NF-kappaBp65 or NF-kappaBp50, or level of expression of beclin-1 or LC3, suggesting that AKT signaling was not down-regulated and the NF-kappaB inflammatory pathway and autophagy were not activated in the COPD muscle. We conclude that muscle atrophy associated with COPD results from the recruitment of specific regulators of ubiquitin-mediated proteolytic pathways and inhibition of muscle growth.
Despite improvements in survival with disease-targeted therapies, the majority of patients with pulmonary arterial hypertension (PAH) have persistent exercise intolerance that results from impaired cardiac function and skeletal muscle dysfunction. Our intent was to understand the molecular mechanisms mediating skeletal muscle dysfunction in PAH. A total of 12 patients with PAH and 10 matched control subjects were assessed. Patients with PAH demonstrated diminished exercise capacity (lower oxygen uptake max, lower anaerobic threshold and higher minute ventilation/CO2) compared with control subjects. Quadriceps muscle cross-sectional area was significantly smaller in patients with PAH. The vastus lateralis muscle was biopsied to enable muscle fiber morphometric assessment and to determine expression levels/activation of proteins regulating (1) muscle mass, (2) mitochondria biogenesis and shaping machinery, and (3) excitation-contraction coupling. Patients with PAH demonstrated a decreased type I/type II muscle fiber ratio, with a smaller cross-sectional area in the type I fibers. Diminished AKT and p70S6 kinase phosphorylation, with increased atrogin-1 and muscle RING-finger protein-1 transcript levels, were evident in the PAH muscle, suggesting engagement of cellular signaling networks stimulating ubiquitin-proteasome-mediated proteolysis of muscle, with concurrent depression of networks mediating muscle hypertrophy. Although there were no differences in expression/activation of proteins associated with mitochondrial biogenesis or fission (MTCO2 [cytochrome C oxidase subunit II]/succinate dehydrogenase flavoprotein subunit A, mitochondrial transcription factor A, nuclear respiratory factor-1/dynamin-related protein 1 phosphorylation), protein levels of a positive regulator of mitochondrial fusion, Mitofusin2, were significantly lower in patients with PAH. Patients with PAH demonstrated increased phosphorylation of ryanodine receptor 1 receptors, suggesting that altered sarcoplasmic reticulum Ca(++) sequestration may impair excitation-contraction coupling in the PAH muscle. These data suggest that muscle dysfunction in PAH results from a combination of muscle atrophy and intrinsically impaired contractility.
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