Skeletal Muscle Loss is Associated with TNF Mediated Insufficient Skeletal Myogenic Activation After Burn

Abstract

Muscle loss accompanies severe burn; in this hyper-catabolic state, muscle undergoes atrophy through protein degradation and disuse. Muscle volume is related to the relative rates of cellular degradation and myogenesis. We hypothesize that muscle atrophy after injury is in part due to insufficient myogenesis associated with the hyper-inflammatory response. The aim of the study is to investigate the role of skeletal myogenesis and muscle cell homeostasis in response to severe burn. Twenty-eight male C57BL6 mice received 25% TBSA scald. Gluteus muscle from these animals was analysed at day 1, 3, 7 and 14 after injury. Six additional animals without burn served as controls. We showed muscle wet weight and protein content decreased at day 3 and 7 after burn, with elevated TNF mRNA expression (p< 0.05). Increased cell death was observed through TUNEL staining, and cleaved caspase-3 levels reached a peak in muscle lysate at day 3 (p < 0.05). The cell proliferation marker PCNA significantly increased after burn, associated with increased gene and protein expression of myogenesis markers Pax7 and myogenin. However, desmin mRNA expression and the ratio of desmin to PCNA protein expression significantly decreased at day 7 (p < 0.05). In vitro, the ratio of desmin to PCNA protein expression significantly decreased in C2C12 murine myoblasts after TNF-α stimulation for 24 hours. We showed that severe burn induces both increased cell death and proliferation. However, myogenesis does not counterbalance increased cell death after burn. Data suggest insufficient myogenesis might be associated with pro-inflammatory mediator TNF activity.

Altered satellite cell dynamics accompany skeletal muscle atrophy during chronic illness, disuse, and aging

“…Burn injury-induced myounclear turnover and myofiber regeneration require adequate and appropriate satellite cell activity and suggest a critical role for satellite cells in skeletal muscle atrophy and recovery following burn trauma. Similar findings reported by Song et al show activation of satellite cells alongside myonuclear apoptosis in mouse muscle following a scald burn (19**). However, the observed myogenesis post-scald likely does not counterbalance the increased cell death after burn, contributing to burn-induced cachexia (19**).…”

“…Similar findings reported by Song et al show activation of satellite cells alongside myonuclear apoptosis in mouse muscle following a scald burn (19**). However, the observed myogenesis post-scald likely does not counterbalance the increased cell death after burn, contributing to burn-induced cachexia (19**). Additionally, inflammation through tumor necrosis factor-α may attenuate the myogenic response to a thermal injury, mitigating the recovery of atrophied muscle (19**).…”

“…However, the observed myogenesis post-scald likely does not counterbalance the increased cell death after burn, contributing to burn-induced cachexia (19**). Additionally, inflammation through tumor necrosis factor-α may attenuate the myogenic response to a thermal injury, mitigating the recovery of atrophied muscle (19**). Findings from Corrick et al .…”

Burn Serum Stimulates Myoblast Cell Death Associated with IL-6-Induced Mitochondrial Fragmentation

“…We previously observed that TNF plays a role in insufficient myogenic activation, contributing to muscle mass loss after burn (33). A recent study from Ueki’s report showed elevated fibrinogen levels in plasma-related muscle wasting in burn mice.…”

Myeloid cell‐derived tumor necrosis factor‐alpha promotes sarcopenia and regulates muscle cell fusion with aging muscle fibers

“…TNF‐α increases in the serum of men during aging (Léger, Derave, Bock, Hespel, & Russell, 2008) which correlates with the loss of muscle mass and strength (Greiwe, Cheng, Rubin, Yarasheski, & Semenkovich, 2001; Visser et al, 2002). Moreover, in other models of muscle atrophy that include cachexia and injury‐induced muscle atrophy, administration of exogenous TNF‐α to mice decreases muscle mass and regenerative capacity (Coletti, Moresi, Adamo, Molinaro, & Sassoon, 2005; Song, Saeman, Libero, & Wolf, 2015). Those data suggest that macrophage‐secreted TNF‐α may play an important role in muscle aging.…”