Abstract
The pathophysiological response to a severe burn injury involves a robust increase in circulating inflammatory/endocrine factors and a hypermetabolic state, both of which contribute to prolonged skeletal muscle atrophy. In order to characterize the role of circulating factors in muscle atrophy following a burn injury, human skeletal muscle satellite cells were grown in culture and differentiated to myoblasts/myotubes in media containing serum from burn patients or healthy, age, and sex-matched controls. While incubation in burn serum did not affect NFκB signaling, cells incubated in burn serum displayed a transient increase in STAT3 phosphorlyation (Tyr705) after 48 h of treatment with burn serum (≈ + 70%; P < 0.01), with these levels returning to normal by 96 h. Muscle cells differentiated in burn serum displayed reduced myogenic fusion signaling (phospho-STAT6 (Tyr641), ≈−75%; ADAM12, ≈-20%; both P < 0.01), and reduced levels of myogenin (≈−75%; P < 0.05). Concomitantly, myotubes differentiated in burn serum demonstrated impaired myogenesis (assessed by number of nuclei/myotube). Incubation in burn serum for 96 h did not increase proteolytic signaling (assessed via caspase-3 and ubiquitin levels), but reduced anabolic signaling [p-p70S6k (Ser421/Thr424), −30%; p-rpS6 (Ser240/244), ≈-50%] and impaired protein synthesis (−24%) (P < 0.05). This resulted in a loss of total protein content (−18%) and reduced cell size (−33%) (P < 0.05). Overall, incubation of human muscle cells in serum from burn patients results in impaired myogenesis and reduced myotube size, indicating that circulating factors may play a significant role in muscle loss and impaired muscle recovery following burn injury.
Highlights
Severe burn injury affecting greater than 20% of the total body surface area (TBSA) causes a robust inflammatory response and an increased metabolic demand which contribute to rapid skeletal muscle catabolism and lead to long-term muscle wasting
By 96 h, there was a slight increase in total STAT3 protein content (+15%; P < 0.001) in cells treated with burn serum
Using an in vitro system, we show that serum obtained from burn patients significantly reduces myoblast differentiation and fusion, and myotube size in healthy primary human muscle cells
Summary
Severe burn injury affecting greater than 20% of the total body surface area (TBSA) causes a robust inflammatory response and an increased metabolic demand which contribute to rapid skeletal muscle catabolism and lead to long-term muscle wasting (reviewed in Wolfe, 1981; Pereira et al, 2005; Porter et al, 2013). The hypermetabolic state in burn patients is characterized by increased body temperature, resting energy expenditure, glycogenolysis, proteolysis, lipolysis, and futile substrate cycling (Wilmore and Aulick, 1978; Herndon and Tompkins, 2004), which can contribute to significant muscle protein degradation. These patients are under the burden of a hyperinflammatory state, characterized by a substantial rise in pro-inflammatory cytokines [e.g., interleukin (IL)-6, tumor necrosis factor (TNF)-α], many of which have negative effects on muscle regeneration/growth (Jeschke et al, 2008; Merritt et al, 2012). These patients had robust elevations in circulating cytokines (up to 70-fold greater than control), as well as elevated inflammatory muscle gene expression (Merritt et al, 2012, 2013b), suggesting that systemic factors may play a key role in muscle wasting in burn patients
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