Severe
burn injuries lead to a prolonged hypercatabolic state resulting in dramatic loss of skeletal muscle mass. Postburn muscle loss is well documented but the molecular signaling cascade preceding
atrophy is not. The purpose of this study is to determine the response to
burn injury of signaling pathways driving muscle
inflammation and
protein metabolism. Muscle biopsies were collected in the early flow phase after
burn injury from the vastus lateralis of a noninjured leg in patients with 20 to 60% TBSA
burns and compared with uninjured, matched controls. Circulating levels of proinflammatory
cytokines were also compared. Immunoblotting was performed to determine the
protein levels of key signaling components for translation initiation, proteolysis, and
tumor necrosis factor/
nuclear factor kappa B (NFκB)and
interleukin (IL)-6/STAT3 signaling.
Burn subjects had significantly higher levels of circulating proinflammatory
cytokines, with no difference in muscle STAT3 activity and lower NFκB activity. No differences were found in any translational signaling components. Regarding proteolytic signaling in
burn, calpain-2 was 47% higher,
calpastatin tended to be lower, and total ubiquitination was substantially higher. Surprisingly, a systemic proinflammatory response 3 to 10 days postburn did not lead to elevated muscle STAT3 or NFκB signaling. Signaling molecules governing translation initiation were unaffected, whereas indices of
calcium-mediated proteolysis and
ubiquitin-
proteasome activity were upregulated. These novel findings are the first in humans to suggest that the net catabolic effect of
burn injury in skeletal muscle (ie,
atrophy) may be mediated, at least during the early flow phase, almost entirely by an increased proteolytic activity in the absence of suppressed
protein synthesis signaling.