Abstract
Not only has pamidronate been shown to prevent inflammation associated bone resorption following burn injury, it also reduces protein breakdown in muscle. The aim of this study was to identify the molecular mechanisms responsible for muscle mass rescue in pamidronate treated compared to placebo/standard of care-treated burn patients. Mature myotubes, generated by differentiating murine C2C12 myoblasts, were exposed for 48 h to 1 or 5% serum obtained from 3 groups of children: normal unburned, burned receiving standard of care, and burned receiving standard of care with pamidronate. Exposure to serum from burned patients caused dose-dependent myotube atrophy compared to normal serum as expected based on previous observations of muscle atrophy induced by burn injury in humans and animals. The size of C2C12 myotubes was partially protected upon exposure to the serum from patients treated with pamidronate correlating with the rescue of muscle size previously observed in these patients. At the molecular signaling level, serum from both pamidronate and non-pamidronate-treated burn patients increased pSTAT3/STAT3 and pERK1/2/ERK1/2 compared to normal serum with no significant differences between the two groups of burn patients indicating elevated production of inflammatory cytokines. However, serum from pamidronate-treated patients restored the phosphorylation of AKT and mTOR and reduced protein ubiquitination when compared to burn serum alone, suggesting a prevention of muscle catabolism and a restoration of muscle anabolism. Myotube atrophy induced by burn serum was partially rescued after exposure to a pan anti-TGFβ-1/2/3 antibody, suggesting that this signaling pathway is partially responsible for the atrophy and that bisphosphonate protection of bones from resorption during burn injury prevents the release of muscle pro-catabolic factors such as TGFβ into the circulation.
Highlights
Unintentional burn injury in the pediatric population is one of the common causes of mortality and morbidity, representing the fourth cause of death in the United States according to the World Health Organization [1]
In order to assess the effects of the serum derived from severely burned children on myotube morphology, fully differentiated C2C12 myotubes were exposed to 1% (Figure 1A) or 5% (Figure 1B) of N, B, or B+P serum
In order to investigate whether the myotube phenotype observed following B or B+P serum exposure was associated with the modulation of pro-atrophic signaling pathways, the level of proteins associated with protein catabolism was assessed
Summary
Unintentional burn injury in the pediatric population is one of the common causes of mortality and morbidity, representing the fourth cause of death in the United States according to the World Health Organization [1]. Muscle wasting results in a negative muscle protein balance, reduction of muscle mass followed by a functional deficit. This event begins acutely but is sustained over the first year post-burn and can impair rehabilitation compromising the recovery [7]. During the acute phase post-burn, the balance between protein synthesis and degradation is impaired, leading to skeletal muscle atrophy [8]. This alteration seems to be predominantly mediated by the hyperactivation of the ATP-ubiquitin-proteasome system through the inflammatory response [9]. The incidence of post-burn fractures is elevated in children and estimated at 15% [12]
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