Optimal length, calcium sensitivity and twitch characteristics of skeletal muscles from mice with a deletion in N2A titin.

During isometric contractions, the optimal length of skeletal muscles increases with decreasing activation. The underlying mechanism for this phenomenon is thought to be linked to length dependence of Ca sensitivity. Muscular dystrophy with myositis (), a recessive titin mutation in mice, was used as a tool to study the role of titin in activation dependence of optimal length and length dependence of Ca sensitivity. We measured the shift in optimal length between tetanic and twitch stimulation in and wild-type muscles, and the length dependence of Ca sensitivity at short and long sarcomere lengths in and wild-type fiber bundles. The results indicate that the mutation leads to a loss of activation dependence of optimal length without the expected change in length dependence of Ca sensitivity, demonstrating that these properties are not linked, as previously suggested. Furthermore, muscles produced maximum tetanic stress during sub-optimal filament overlap at lengths similar to twitch contractions in both genotypes, but the difference explains less than half of the observed reduction in active force of muscles. muscles also exhibited increased electromechanical delay, contraction and relaxation times, and decreased rate of force development in twitch contractions. We conclude that the small deletion in titin associated with in skeletal muscles alters force production, suggesting an important regulatory role for titin in active force production. The molecular mechanisms for titin's role in regulating muscle force production remain to be elucidated.