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Proc Natl Acad Sci U S A. 2019 Apr 23;116(17):8397-8402. doi: 10.1073/pnas.1813351116. Epub 2019 Apr 8.

CAP2 deficiency delays myofibril actin cytoskeleton differentiation and disturbs skeletal muscle architecture and function.

Author information

1
Molecular Neurobiology Group, Institute of Physiological Chemistry, University of Marburg, 35032 Marburg, Germany.
2
Laboratory of Synaptogenesis, Nencki Institute of Experimental Biology PAS, 02-093 Warsaw, Poland.
3
Department of Pathology and Immunology, University of Geneva, 1211 Geneva, Switzerland.
4
Institute of Neuropathology, University of Marburg, 35032 Marburg, Germany.
5
Molecular Neurobiology Group, Institute of Physiological Chemistry, University of Marburg, 35032 Marburg, Germany; marco.rust@staff.uni-marburg.de.
6
Center for Mind, Brain and Behavior, Research Campus of Central Hessen, 35032 Marburg, Germany.
7
DFG Research Training Group "Membrane Plasticity in Tissue Development and Remodeling," GRK 2213, University of Marburg, 35032 Marburg, Germany.

Abstract

Actin filaments (F-actin) are key components of sarcomeres, the basic contractile units of skeletal muscle myofibrils. A crucial step during myofibril differentiation is the sequential exchange of α-actin isoforms from smooth muscle (α-SMA) and cardiac (α-CAA) to skeletal muscle α-actin (α-SKA) that, in mice, occurs during early postnatal life. This "α-actin switch" requires the coordinated activity of actin regulators because it is vital that sarcomere structure and function are maintained during differentiation. The molecular machinery that controls the α-actin switch, however, remains enigmatic. Cyclase-associated proteins (CAP) are a family of actin regulators with largely unknown physiological functions. We here report a function for CAP2 in regulating the α-actin exchange during myofibril differentiation. This α-actin switch was delayed in systemic CAP2 mutant mice, and myofibrils remained in an undifferentiated stage at the onset of the often excessive voluntary movements in postnatal mice. The delay in the α-actin switch coincided with the onset of motor function deficits and histopathological changes including a high frequency of type IIB ring fibers. Our data suggest that subtle disturbances of postnatal F-actin remodeling are sufficient for predisposing muscle fibers to form ring fibers. Cofilin2, a putative CAP2 interaction partner, has been recently implicated in myofibril actin cytoskeleton differentiation, and the myopathies in cofilin2 and CAP2 mutant mice showed striking similarities. We therefore propose a model in which CAP2 and cofilin2 cooperate in actin regulation during myofibril differentiation.

KEYWORDS:

6p22.3; Srv2; actin dynamics; ringbinden; spiral annulets

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