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(Circulation Research. 2009;104:1021.)
© 2009 American Heart Association, Inc.

Integrative Physiology

Biochemical and Mechanical Dysfunction in a Mouse Model of Desmin-Related Myopathy

Alina Maloyan, Hanna Osinska, Jan Lammerding, Richard T. Lee, Oscar H. Cingolani, David A. Kass, John N. Lorenz, Jeffrey Robbins

From the Division of Molecular Cardiovascular Biology (A.M., H.O., J.R.), Cincinnati Children’s Hospital Medical Center, Ohio; Biological Engineering Division (J.L., R.T.L.), Massachusetts Institute of Technology, Cambridge; Cardiovascular Division (J.L., R.T.L.), Brigham and Women’s Hospital, Cambridge, Mass; Division of Cardiology (O.H.C., D.A.K.), Department of Medicine, The Johns Hopkins Medical Institutions, Baltimore, Md; and Molecular and Cellular Physiology (J.N.L.), University of Cincinnati, Ohio.

Correspondence to Jeffrey Robbins, MLC 7020, Cincinnati Children’s Hospital Medical Center, 240 Albert Sabin Way, Cincinnati, OH 45229-3039. E-mail jeff.robbins{at}cchmc.org

An R120G mutation in B-crystallin (CryAB^R120G) causes desmin-related myopathy (DRM). In mice with cardiomyocyte-specific expression of the mutation, CryAB^R120G-mediated DRM is characterized by CryAB and desmin accumulations within cardiac muscle, mitochondrial deficiencies, activation of apoptosis, and heart failure (HF). Excessive production of reactive oxygen species (ROS) is often a hallmark of HF and treatment with antioxidants can sometimes prevent the progression of HF in terms of contractile dysfunction and cardiomyocyte survival. It is unknown whether blockade of ROS is beneficial for protein misfolding diseases such as DRM. We addressed this question by blocking the activity of xanthine oxidase (XO), a superoxide-generating enzyme that is upregulated in our model of DRM. The XO inhibitor oxypurinol was administered to CryAB^R120G mice for a period of 1 or 3 months. Mitochondrial function was dramatically improved in treated animals in terms of complex I activity and conservation of mitochondrial membrane potential. Oxypurinol also largely restored normal mitochondrial morphology. Surprisingly, however, cardiac contractile function and cardiac compliance were unimproved, indicating that the contractile deficit might be independent of mitochondrial dysfunction and the initiation of apoptosis. Using magnetic bead microrheology at the single cardiomyocyte level, we demonstrated that sarcomeric disarray and accumulation of the physical aggregates resulted in significant changes in the cytoskeletal mechanical properties in the CryAB^R120G cardiomyocytes. Our findings indicate that oxypurinol treatment largely prevented mitochondrial deficiency in DRM but that contractility was not improved because of mechanical deficits in passive cytoskeletal stiffness.

Key Words: mitochondria • oxidative stress • antioxidants • protein misfolding • reactive oxygen species