The muscle LIM protein (MLP) and cofilin 2 (CFL2) are important regulators of 
striated myocyte function. Mutations in the corresponding genes have been 
directly associated with severe human cardiac and skeletal myopathies, and 
aberrant expression patterns have often been observed in affected muscles. 
Herein, we have investigated whether MLP and CFL2 are involved in common 
molecular mechanisms, which would promote our understanding of disease 
pathogenesis. We have shown for the first time, using a range of biochemical and 
immunohistochemical methods, that MLP binds directly to CFL2 in human cardiac 
and skeletal muscles. The interaction involves the inter-LIM domain, amino acids 
94 to 105, of MLP and the amino-terminal domain, amino acids 1 to 105, of CFL2, 
which includes part of the actin depolymerization domain. The MLP/CFL2 complex 
is stronger in moderately acidic (pH 6.8) environments and upon CFL2 
phosphorylation, while it is independent of Ca(2+) levels. This interaction has 
direct implications in actin cytoskeleton dynamics in regulating CFL2-dependent 
F-actin depolymerization, with maximal depolymerization enhancement at an 
MLP/CFL2 molecular ratio of 2:1. Deregulation of this interaction by 
intracellular pH variations, CFL2 phosphorylation, MLP or CFL2 gene mutations, 
or expression changes, as observed in a range of cardiac and skeletal 
myopathies, could impair F-actin depolymerization, leading to sarcomere 
dysfunction and disease.