Corona BT, Rouviere C, Hamilton SL, Ingalls CP. Eccentric contractions do not induce rhabdomyolysis in malignant hyperthermia susceptible mice. J Appl Physiol 105: 1542-1553, 2008. First published September 11, 2008 doi:10.1152/japplphysiol.90926.2008.-Recent studies suggest a link between exercise-induced rhabdomyolysis and mutations of the ryanodine receptor (RYR1) associated with malignant hyperthermia (MH). We hypothesized that MH-susceptible mice (RYR1 Y522S/wt ) would exhibit greater anterior crural muscle [tibialis anterior (TA) and extensor digitorum longus (EDL) muscles] damage and strength deficits following the performance of a single or repeated bouts of eccentric contractions compared with wild-type (WT) mice. After a single injury bout, RYR1Y522S/wt mice produced more isometric torque than WT mice immediately and 3 and 7 days postinjury. Moreover, EDL muscle isometric specific force deficits were fully recovered for RYR1 Y522S/wt but not WT mice 14 days postinjury. The percentage of fibers in TA muscle exhibiting signs of muscle damage 7 and 14 days postinjury were at least three times less in RYR1 Y522S/wt than in WT mice. Uninjured and injured EDL muscle from RYR1 Y522S/wt mice also displayed greater S-glutathionylation of RYR1 than that from WT mice. During the weekly injury bouts, torque production by RYR1 Y522S/wt mice was fully recovered before the third and fourth injury bouts, whereas torque was still reduced for WT mice. Three days after multiple injury bouts, there were Ďł50% fewer fibers exhibiting signs of muscle damage in RYR1 Y522S/wt than in WT TA muscle. These findings indicate that the RYR1 Y522S/wt mutation protects skeletal muscle from exercise-induced muscle injury and do not support a direct association between MH susceptibility and contraction-induced rhabdomyolysis when core temperature is maintained at lower physiological temperatures during exercise.contraction-induced muscle injury/damage MALIGNANT HYPERTHERMIA (MH) is a pharmacogenetic disorder, whereupon administration of halogenated anesthetic to a genetically predisposed individual can induce a hypermetabolic episode. A MH episode can be characterized by increases in body temperature, skeletal muscle rigidity, hyperkalemia, metabolic acidosis, and rhabdomyolysis and, potentially, culminates in organ failure and death (38). Mutations associated with MH can involve the sarcoplasmic reticulum (SR) Ca 2Ď© release channel (ryanodine receptor 1; RYR1) and promote an inordinate release of Ca 2Ď© from the SR in response to halogenated anesthetics (e.g., halothane and isoflurane) and caffeine (3, 6).Recently, a mouse model was generated with a mutation (Y522S) in RYR1 that has been associated with MH in humans (6, 16). Heterozygous expression of this mutation (RYR1 Y522S/wt ) has been shown previously to increase the sensitivity of RYR1 to halothane and caffeine in isolated soleus muscle and to electrical stimulation in myotubes, as well as to increase the resting cytosolic Ca 2Ď© concentrations in myotubes and single soleus muscle...