| First Author | Ochala J | Year | 2013 |
| Journal | Hum Mol Genet | Volume | 22 |
| Issue | 21 | Pages | 4398-404 |
| PubMed ID | 23784376 | Mgi Jnum | J:202282 |
| Mgi Id | MGI:5517772 | Doi | 10.1093/hmg/ddt289 |
| Citation | Ochala J, et al. (2013) Skeletal and cardiac alpha-actin isoforms differently modulate myosin cross-bridge formation and myofibre force production. Hum Mol Genet 22(21):4398-404 |
| abstractText | Multiple congenital myopathies, including nemaline myopathy, can arise due to mutations in the ACTA1 gene encoding skeletal muscle alpha-actin. The main characteristics of ACTA1 null mutations (absence of skeletal muscle alpha-actin) are generalized skeletal muscle weakness and premature death. A mouse model (ACTC(Co)/KO) mimicking these conditions has successfully been rescued by transgenic over-expression of cardiac alpha-actin in skeletal muscles using the ACTC gene. Nevertheless, myofibres from ACTC(Co)/KO animals generate less force than normal myofibres (-20 to 25%). To understand the underlying mechanisms, here we have undertaken a detailed functional study of myofibres from ACTC(Co)/KO rodents. Mechanical and X-ray diffraction pattern analyses of single membrane-permeabilized myofibres showed, upon maximal Ca(2+) activation and under rigor conditions, lower stiffness and disrupted actin-layer line reflections in ACTC(Co)/KO when compared with age-matched wild-types. These results demonstrate that in ACTC(Co)/KO myofibres, the presence of cardiac alpha-actin instead of skeletal muscle alpha-actin alters actin conformational changes upon activation. This later finely modulates the strain of individual actomyosin interactions and overall lowers myofibre force production. Taken together, the present findings provide novel primordial information about actin isoforms, their functional differences and have to be considered when designing gene therapies for ACTA1-based congenital myopathies. |
