O.34Leiomodin-3 (LMOD3) deficiency affects contractile function and structure of fast muscle fibres

Leiomodin-3 (LMOD3), encoded by LMOD3, is a member of the tropomodulin protein family localising predominantly near striated muscle thin filament pointed ends. Recently, the critical role of LMOD3 for skeletal muscle function became apparent when mutations in this gene were found to cause a particularly severe form of nemaline myopathy characterised by neonatally lethal generalised muscle weakness. Currently, LMOD3 is thought to be essential for the structure of the thin filament in skeletal muscle, however, knowledge about LMOD3s function and the cause of weakness in LMOD3 patients is limited. We aim to shed light on LMOD3s role in skeletal muscle by investigating the ultrastructure and contractile properties of skeletal muscle from Lmod3 knock-out (KO) mice. Contractile mechanics of intact extensor digitorum longus (EDL) and soleus muscles as well as contractile performance of permeabilised single muscle fibres showed that fast type 2a and 2b fibres were affected by LMOD3 absence whereas slow type 1 fibres appeared to have preserved contractile function. Additionally, fibre type analysis of Lmod3 KO tibialis anterior muscle showed selective atrophy of 2b fibres and a shift towards a slower fibre typing profile. Our research suggests LMOD3 deficiency causes impaired skeletal muscle contraction in fast myofibers, whereas slow type 1 fibres are unaffected. Additionally, the selective atrophy of 2b fibres indicates that LMOD3 is critical for the biology of this fibre type. The present study highlights a novel role for LMOD proteins during muscle contraction, in particular in fast 2a and 2b myofibres. It remains to be established how these findings translate to LMOD3 patients, but it is possible that LMOD3 loss directly influence the contractile mechanics in LMOD3 patients resulting in muscle weakness.