Nemaline myopathy (NM) is the most common congenital myopathy and is caused by 
mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), 
TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin). 20-25% of NM cases 
carry ACTA1 defects and these particular mutations usually induce substitutions 
of single residues in the actin protein. Despite increasing clinical and 
scientific interest, the contractile consequences of these subtle amino acid 
substitutions remain obscure. To decipher them, in the present study, we 
originally recorded and analysed the mechanics as well as the X-ray diffraction 
patterns of human membrane-permeabilized single muscle fibres with a particular 
peptide substitution in actin, i.e. p.Phe352Ser. Results unravelled an 
unexpected cascade of molecular and cellular events. During contraction, 
p.Phe352Ser greatly enhances the strain of individual cross-bridges. 
Paradoxically, p.Phe352Ser also slightly lowers the number of cross-bridges by 
altering the rate of myosin head attachment to actin monomers. Overall, at the 
cell level, these divergent mechanisms conduct to an improved steady-state force 
production. Such results provide new surprising scientific insights and crucial 
information for future therapeutic strategies.