Myocardial oxidative stress, osteogenic phenotype, and energy metabolism are differentially involved in the initiation and early progression of δ-sarcoglycan-null cardiomyopathy

Abstract

Dilated cardiomyopathy (DCM) is a common cause of heart failure, and identification of early pathogenic events occurring prior to the onset of cardiac dysfunction is of mechanistic, diagnostic, and therapeutic importance. The work characterized early biochemical pathogenesis in TO2 strain hamsters lacking δ-sarcoglycan. Although the TO2 hamster heart exhibits normal function at 1 month of age (presymptomatic stage), elevated levels of myeloperoxidase, monocyte chemotactic protein-1, malondialdehyde, osteopontin, and alkaline phosphatase were evident, indicating the presence of inflammation, oxidative stress, and osteogenic phenotype. These changes were localized primarily to the myocardium. Derangement in energy metabolism was identified at the symptomatic stage (4 month), and is marked by attenuated activity and expression of pyruvate dehydrogenase E1 subunit, which catalyzes the rate-limiting step in aerobic glucose metabolism. Thus, this study illustrates differential involvement of oxidative stress, osteogenic phenotype, and glucose metabolism in the initiation and early progression of δ-sarcoglycan-null DCM.

Secreted Frizzled-related protein 2 as a target in antifibrotic therapeutic intervention

“…The ␦-sarcoglycan-null TO2 strain hamster develops congestive heart failure resembling that seen in the general population of heart failure patients (13,37,39,50). Functional deterioration of the TO2 hamster heart is caused by progressive loss of cardiomyocytes, leading to prominent inflammation and fibrosis at 5 mo of age (ϳ10% fibrotic area vs. ϳ1% fibrotic area in the normal heart).…”

“…The gene sequence information allows us to design primers to quantify sFRP2 expression by qRT-PCR. Figure 1A shows that the 1-mo TO2 heart, which exhibits normal contractile function (39), displays a slight increase in sFRP2 expression compared with the age-matched F1B strain normal hamster heart. The difference in sFRP2 expression was further amplified at 5 mo (ϳ3-fold increase compared with the F1B heart).…”

Basal Bioenergetic Abnormalities in Skeletal Muscle from Ryanodine Receptor Malignant Hyperthermia-susceptible R163C Knock-in Mice

“…The colorimetric assay is based on the reduction of iodonitrotetrazolium to formazan in an NADH-coupled enzymatic reaction using glyceraldehyde-3-phosphate as substrate (62). Briefly, 3-5 g of skeletal muscle proteins were diluted 1:1 with 2ϫ cell lysis solution and added to a 96-well microplate.…”

Intramuscular VEGF activates an SDF1-dependent progenitor cell cascade and an SDF1-independent muscle paracrine cascade for cardiac repair

“…Four-month-old TO2 cardiomyopathic hamsters (30) were purchased from Bio Breeders. Animals were injected twice per week, over the 4-wk course of the study, in both the left and right hamstrings with either saline or 1 g/kg of recombinant VEGF.…”

“…The failing hamster heart exhibits progressive cardiomyocyte loss (30,41). Histological analysis with terminal deoxynucleotidyl transferase dUTP-mediated nick-end labeling staining to detect Fig.…”