Anti-CAV3 (C-terminal) polyclonal antibody

Defective membrane repair can contribute to the progression of muscular dystrophy. Although mutations in caveolin-3 (Cav3) and dysferlin are linked to muscular dystrophy in human patients, the molecular mechanism underlying the functional interplay between Cav3 and dysferlin in membrane repair of muscle physiology and disease has not been fully resolved. We recently discovered that mitsugumin 53 (MG53), a muscle-specific TRIM (Tri-partite motif) family protein (TRIM72), contributes to intracellular vesicle trafficking and is an essential component of the membrane repair machinery in striated muscle. Here we show that MG53 interacts with dysferlin and Cav3 to regulate membrane repair in skeletal muscle. MG53 mediates active trafficking of intracellular vesicles to the sarcolemma and is required for movement of dysferlin to sites of cell injury during repair patch formation. Mutations in Cav3 (P104L, R26Q) that cause retention of Cav3 in Golgi apparatus result in aberrant localization of MG53 and dysferlin in a dominant-negative fashion, leading to defective membrane repair. Our data reveal that a molecular complex formed by MG53, dysferlin, and Cav3 is essential for repair of muscle membrane damage and also provide a therapeutic target for treatment of muscular and cardiovascular diseases that are linked to compromised membrane repair.

Signal transducer and activator of transcription 3 (STAT3) activation is key for ischemic postconditioning (IPo) to attenuate myocardial ischemia-reperfusion injury (MIRI), but IPo loses cardioprotection in diabetes in which cardiac STAT3 activation is impaired and adiponectin (APN) reduced. We found that IPo increased postischemic cardiomyocyte-derived APN, activated mitochondrial STAT3 (mitoSTAT3), improved mitochondria! function, and attenuated MIRI in wild-type but not in APN knockout (Adipo(-/-)) mice subjected to 30 min coronary occlusion, followed by 2 or 24 h of reperfusion. Hypoxic postconditioning-induced protection against hypoxia/reoxygenation injury was lost in Adipo(-/-) cardiomyocytes but restored by recombinant APN, but this APN beneficial effect was abolished by specific STAT3 or APN receptor 1 (AdipoR1) gene knockdown, or caveolin-3 (Cav3) disruption. APN activated cardiac STAT3 and restored IPo cardioprotection in 4-week diabetic rats where AdipoR1 and Cav3 were functionally interactive but not in 8-week diabetic rats whose cardiac Cav3 was severely reduced and AdipoR1/Cav3 signaling impaired. We concluded that IPo activates mitoSTAT3 through APN/AdipoR1/Cav3 pathway to confer cardioprotection, whereas in diabetes, IPo loses cardioprotection due to impaired APN/AdipoR1/Cav3 signaling. Therefore, effective means that may concomitantly activate APN and repair APN signaling (i.e., AdipoR1/Cav3) in diabetes may represent promising avenues in the treatment of MIRI in diabetes.