Abstract
A novel cardiac-specific transgenic mouse model was generated to identify the physiological consequences of elongated thin filaments during post-natal development in the heart. Remarkably, increasing the expression levels in vivo of just one sarcomeric protein, Lmod2, results in ~10% longer thin filaments (up to 26% longer in some individual sarcomeres) that produce up to 50% less contractile force. Increasing the levels of Lmod2 in vivo (Lmod2-TG) also allows us to probe the contribution of Lmod2 in the progression of cardiac myopathy because Lmod2-TG mice present with a unique cardiomyopathy involving enlarged atrial and ventricular lumens, increased heart mass, disorganized myofibrils and eventually, heart failure. Turning off of Lmod2 transgene expression at postnatal day 3 successfully prevents thin filament elongation, as well as gross morphological and functional disease progression. We show here that Lmod2 has an essential role in regulating cardiac contractile force and function.
Highlights
Contractile force in striated muscles is produced by the concerted interaction between interdigitating actin-based thin filaments and myosin-based thick filaments
Numerous actin-binding proteins have been shown to regulate the lengths of actin filaments from their barbed ends in non-muscle cells; in mammalian cardiac muscle cells, where dynamic regulation of thin filament lengths occurs from the pointed ends in the center of the sarcomere, tropomodulin and leiomodin are the only proteins reported to localize to the pointed ends, and function to maintain thin filament lengths [reviewed in [6,7,8]]
Our laboratory has recently discovered a direct link between leiomodin-2 and human cardiomyopathy based on a case study of an infant with a homozygous Lmod2 nonsense mutation
Summary
Contractile force in striated muscles is produced by the concerted interaction between interdigitating actin-based thin filaments and myosin-based thick filaments. It is known that changes in thin filament lengths are linked to development of cardiac and skeletal myopathies [1,2,3,4,5], how those changes contribute to the pathophysiological mechanism of disease progression has yet to be shown. Numerous actin-binding proteins have been shown to regulate the lengths of actin filaments from their barbed ends in non-muscle cells; in mammalian cardiac muscle cells, where dynamic regulation of thin filament lengths occurs from the pointed ends in the center of the sarcomere, tropomodulin and leiomodin are the only proteins reported to localize to the pointed ends, and function to maintain thin filament lengths [reviewed in [6,7,8]]. Each of three leiomodin isoforms show a predominant expression pattern in different muscle
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
