| First Author | Fujita K | Year | 2025 |
| Journal | Circ Heart Fail | Volume | 18 |
| Issue | 4 | Pages | e011867 |
| PubMed ID | 40066567 | Mgi Jnum | J:364230 |
| Mgi Id | MGI:8169039 | Doi | 10.1161/CIRCHEARTFAILURE.124.011867 |
| Citation | Fujita K, et al. (2025) Combined Loss of Obsc and Obsl1 in Murine Hearts Results in Diastolic Dysfunction, Altered Metabolism, and Deregulated Mitophagy. Circ Heart Fail :e011867 |
| abstractText | BACKGROUND: Muscle proteins of the obscurin protein family play important roles in sarcomere organization and sarcoplasmic reticulum and T-tubule architecture and function. However, their precise molecular functions and redundancies between protein family members as well as their involvement in cardiac diseases remain to be fully understood. METHODS: To investigate the functional roles of Obsc (obscurin) and its close homolog Obsl1 (obscurin-like 1) in the heart, we generated and analyzed knockout mice for Obsc, Obsl1, as well as Obsc/Obsl1 double knockouts. RESULTS: We show that double-knockout mice are viable but show postnatal deficits in cardiac muscle sarcoplasmic reticulum and mitochondrial architecture and function at the microscopic, biochemical, and cellular levels. Altered sarcoplasmic reticulum structure resulted in perturbed calcium cycling, whereas mitochondrial ultrastructure deficits were linked to decreased levels of Chchd3 (coiled-coil-helix-coiled-coil-helix domain containing 3), a Micos (mitochondrial contact site and cristae organizing system) complex protein. Hearts of double-knockout mice also show altered levels of Atg4 proteins, novel Obsl1 interactors, resulting in abnormal mitophagy, and increased unfolded protein response. At the physiological level, loss of obscurin and Obsl1 resulted in a profound delay of cardiac relaxation, associated with metabolic signs of heart failure. CONCLUSIONS: Taken together, our data suggest that Obsc and Obsl1 play crucial roles in cardiac sarcoplasmic reticulum structure, calcium cycling, mitochondrial function, turnover, and metabolism. |
