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Involvement of calpain in myonephropathic metabolic syndrome (MNMS)
Y Tsuji1, J Kambayashi, E Shiba
1Department of Surgery II, Osaka University Medical School, Japan.
Abstract:
Myonephropathic metabolic syndrome (MNMS) is a serious muscle reperfusion injury associated with acute renal failure. The exact pathogenesis of MNMS has not been fully elucidated, nor effective treatment, through the renal failure is thought to be a consequence of rhabdomyolysis. In the present study, the possible involvement of calpain in the lysis was investigated in a MNMS animal model employing a cell permeable calpain antagonist calpeptin. Male rabbits were subjected to bilateral hind leg ischaemia for 5 hours by clamping the distal aorta, followed by reperfusion for 3 hours. Blood pressure, plasma N-acethyl-beta-D-glucosaminidase (NAG) and the presence of myoglobinuria were serially determined. Blood pressure remained constant during the ischemic period but dropped by about 25% immediately after reperfusion. This was significantly attenuated by intraaortic administration of calpeptin. NAG gradually increased during ischemia and during reperfusion and this was also significantly reduced by calpeptin. Myoglobinuria appeared immediately after reperfusion, and was also attenuated by calpeptin. Calpeptin prevented lytic and degenerative changes of the hind leg muscles, determined by light and electron microscopy. Thus it is concluded that activation of calpain in skeletal muscle is an important etiologic factor of MNMS and that the occurrence of MNMS may be prevented by administration of a calpain antagonist.
Insights
Myonephropathic metabolic syndrome (MNMS) involves muscle injury and kidney failure. Calpain inhibition with calpeptin effectively prevented muscle lysis and renal dysfunction in an animal model, suggesting a therapeutic target.
Area of Science:
- Biochemistry
- Nephrology
- Muscle Physiology
Background:
- Myonephropathic metabolic syndrome (MNMS) is a severe condition linking muscle reperfusion injury to acute renal failure.
- The precise mechanisms driving MNMS and effective treatments remain unclear, though rhabdomyolysis is implicated in renal failure.
- Calpain's role in muscle lysis within MNMS has not been fully established.
Purpose of the Study:
- To investigate the potential involvement of calpain in muscle lysis during MNMS.
- To evaluate the efficacy of a cell-permeable calpain antagonist, calpeptin, in an MNMS animal model.
Main Methods:
- An MNMS animal model was created in male rabbits by inducing 5-hour hind leg ischemia followed by 3-hour reperfusion.
- Intraaortic administration of calpeptin was used to assess its effects on blood pressure, plasma N-acetyl-beta-D-glucosaminidase (NAG), and myoglobinuria.
- Muscle tissue was examined using light and electron microscopy to evaluate lytic and degenerative changes.
Main Results:
- Reperfusion caused a significant drop in blood pressure, which was attenuated by calpeptin.
- Plasma NAG levels and myoglobinuria, indicative of muscle damage and renal stress, increased post-reperfusion but were reduced by calpeptin.
- Calpeptin administration prevented muscle lysis and degenerative changes observed in the hind leg muscles.
Conclusions:
- Activation of calpain in skeletal muscle plays a significant role in the etiology of MNMS.
- Administration of calpain antagonists, such as calpeptin, shows promise for preventing MNMS and its associated renal complications.