Skeletal and cardiac αactin isoforms differently modulate myosin cross-bridge formation and myofibre force production
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Skeletal and cardiac αactin isoforms differently modulate myosin cross-bridge formation and myofibre force production. / Ochala, Julien; Iwamoto, Hiroyuki; Ravenscroft, Gianina; Laing, Nigel G.; Nowak, Kristen J.
I: Human Molecular Genetics, Bind 22, Nr. 21, ddt289, 11.2013, s. 4398-4404.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - Skeletal and cardiac αactin isoforms differently modulate myosin cross-bridge formation and myofibre force production
AU - Ochala, Julien
AU - Iwamoto, Hiroyuki
AU - Ravenscroft, Gianina
AU - Laing, Nigel G.
AU - Nowak, Kristen J.
PY - 2013/11
Y1 - 2013/11
N2 - Multiple congenital myopathies, including nemaline myopathy, can arise due to mutations in the ACTA1 gene encoding skeletal muscle a-actin. The main characteristics of ACTA1 null mutations (absence of skeletal muscle a-actin) are generalized skeletal muscle weakness and premature death. A mouse model (ACTCCo/KO) mimicking these conditions has successfully been rescued by transgenic over-expression of cardiac a-actin in skeletal muscles using the ACTC gene. Nevertheless, myofibres from ACTCCo/KO animals generate less force than normal myofibres (220 to 25%). To understand the underlying mechanisms, here we have undertaken a detailed functional study of myofibres from ACTCCo/KO rodents. Mechanical and X-ray diffraction pattern analyses of single membrane-permeabilized myofibres showed, upon maximal Ca21 activation and under rigor conditions, lower stiffness and disrupted actin-layer line reflections in ACTCCo/KO when compared with age-matched wild-types. These results demonstrate that in ACTCCo/KO myofibres, the presence of cardiac a-actin instead of skeletal muscle a-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 forACTA1-based congenital myopathies.
AB - Multiple congenital myopathies, including nemaline myopathy, can arise due to mutations in the ACTA1 gene encoding skeletal muscle a-actin. The main characteristics of ACTA1 null mutations (absence of skeletal muscle a-actin) are generalized skeletal muscle weakness and premature death. A mouse model (ACTCCo/KO) mimicking these conditions has successfully been rescued by transgenic over-expression of cardiac a-actin in skeletal muscles using the ACTC gene. Nevertheless, myofibres from ACTCCo/KO animals generate less force than normal myofibres (220 to 25%). To understand the underlying mechanisms, here we have undertaken a detailed functional study of myofibres from ACTCCo/KO rodents. Mechanical and X-ray diffraction pattern analyses of single membrane-permeabilized myofibres showed, upon maximal Ca21 activation and under rigor conditions, lower stiffness and disrupted actin-layer line reflections in ACTCCo/KO when compared with age-matched wild-types. These results demonstrate that in ACTCCo/KO myofibres, the presence of cardiac a-actin instead of skeletal muscle a-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 forACTA1-based congenital myopathies.
UR - http://www.scopus.com/inward/record.url?scp=84885813069&partnerID=8YFLogxK
U2 - 10.1093/hmg/ddt289
DO - 10.1093/hmg/ddt289
M3 - Journal article
C2 - 23784376
AN - SCOPUS:84885813069
VL - 22
SP - 4398
EP - 4404
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 21
M1 - ddt289
ER -
ID: 245663399