title: Biochemical and mechanical dysfunction in a mouse model of desmin-related myopathy.
abstract: An R120G mutation in alphaB-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.
authors.affiliation: Division of Molecular Cardiovascular Biology, Cincinnati Children's Hospital Medical Center, Ohio 45229-3039, USA.
authors.forename: Alina
authors.initials: A
authors.lastname: Maloyan
authors.forename: Hanna
authors.initials: H
authors.lastname: Osinska
authors.forename: Jan
authors.initials: J
authors.lastname: Lammerding
authors.forename: Richard T
authors.initials: RT
authors.lastname: Lee
authors.forename: Oscar H
authors.initials: OH
authors.lastname: Cingolani
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: John N
authors.initials: JN
authors.lastname: Lorenz
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Robbins
mesh_terms: D000818:Animals; D017209:Apoptosis; D009202:Cardiomyopathies / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D003187:Compliance; D003893:Desmin / Q000378:metabolism*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D018056:Hemorheology; D053078:Membrane Potential, Mitochondrial; D051379:Mice; D008822:Mice, Transgenic; D008929:Mitochondria, Heart / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D009154:Mutation; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress; D010117:Oxypurinol / Q000494:pharmacology; D017510:Protein Folding; D017382:Reactive Oxygen Species / Q000378:metabolism; D012518:Sarcomeres / Q000378:metabolism; D016277:Ventricular Function, Left / Q000187:drug effects; D014969:Xanthine Oxidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D038203:alpha-Crystallin B Chain / Q000235:genetics / Q000378:metabolism
chemical_list: C525420:Cryab protein, mouse; D003893:Desmin; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D017382:Reactive Oxygen Species; D038203:alpha-Crystallin B Chain; D014969:Xanthine Oxidase; D010117:Oxypurinol