THE 1999 MOYER AWARD Burn Injury Induces Skeletal Muscle Apoptosis and the Activation of Caspase Pathways in Rats

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Abstract

Burn injury induces many metabolic disorders, including altered protein kinetics with muscle weakness. The skeletal muscle weakness that occurs as a result of the loss of muscle mass causes hypoventilation and dependence on respirators, a condition that increases morbidity and mortality. The presence or absence of apoptosis in muscle, which can be a cause of the loss of muscle mass, was studied in rats after they had received scald burns to 40% of their body surface areas. The potential pro–apoptotic pathways that were activated were also examined. The burn injury produced did not directly destroy the muscle beneath; muscles just beneath the burned surface showed dramatic apoptotic changes according to assessments with the cell death enzyme–linked immunosorbent assay and in situ TdT–mediated dUTP–X nick–end labeling staining. The extent of apoptosis reached a peak on postburn days 3 and 7. Of note is that apoptosis was also confirmed in muscles at sites distant from the burn injury (eg, tibialis anterior) on both postburn days 3 and 7, a condition that is suggestive of the systemic effects of pro–apoptotic factors. To show that heat itself causes the initiation of the pro–apoptotic signaling, muscle–derived C2C12 cells were subjected to heat treatment at 55°C. Ceramide, a key apoptotic second messenger, was observed to increase in the caveolae fraction but not in non–caveolae fraction of these muscle cells. In muscle tissue from burned rats, stress–activated protein kinase (a downstreamsignaling kinase of ceramide) was activated soon after burn injury; this finding is consistent with the hypothesis that ceramide plays a role in burn–induced apoptosis. Caspase–1, –3, and –9, important final apoptotic enzymes involved with the downstream signaling of stress–activated protein kinase, were also activated after burn injury in muscle tissue from burned rats. These findings confirm the hypothesis that apoptosis occurs in skeletal muscle and that major apoptot ic pathways are activated after a burn injury. Further characterization of these apoptotic signaling cascades may provide new therapeutic targets for the prevention of burn–induced muscle wasting. (J Burn Care Rehabil 1999;20:462–70)

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