The
Proline,
Glutamate,
Valine and
Lysine-rich (PEVK) region of
titin constitutes an entropic spring that provides passive tension to striated muscle. To study the functional and structural repercussions of a small reduction in the size of the PEVK region, we investigated skeletal muscles of a mouse with the constitutively expressed C-terminal PEVK exons 219-225 deleted, the TtnΔ219-225 model (MGI: TtnTM 2.1Mgot ). Based on this deletion, passive tension in skeletal muscle was predicted to be increased by ∼17% (sarcomere length 3.0 μm). In contrast, measured passive tension (sarcomere length 3.0 μm) in both soleus and EDL muscles was increased 53 ± 11% and 62 ± 4%, respectively. This unexpected increase was due to changes in
titin, not to alterations in the extracellular matrix, and is likely caused by co-expression of two
titin isoforms in TtnΔ219-225 muscles: a larger
isoform that represents the TtnΔ219-225 N2A
titin and a smaller
isoform, referred to as N2A2. N2A2 represents a splicing adaption with reduced expression of spring
element exons, as determined by
titin exon microarray analysis. Maximal tetanic tension was increased in TtnΔ219-225 soleus muscle (WT 240 ± 9; TtnΔ219-225 276 ± 17 mN/mm2), but was reduced in EDL muscle (WT 315 ± 9; TtnΔ219-225 280 ± 14 mN/mm2). The changes in active tension coincided with a switch toward slow fiber types and, unexpectedly, faster kinetics of tension generation and relaxation. Functional overload (FO; ablation) and hindlimb suspension (HS; unloading) experiments were also conducted. TtnΔ219-225 mice showed increases in both longitudinal
hypertrophy (increased number of sarcomeres in series) and cross-sectional
hypertrophy (increased number of sarcomeres in parallel) in response to FO and attenuated cross-sectional
atrophy in response to HS. In summary, slow- and fast-twitch muscles in a mouse model devoid of
titin's PEVK exons 219-225 have high passive tension, due in part to alterations elsewhere in splicing of
titin's spring region, increased kinetics of tension generation and relaxation, and altered trophic responses to both functional overload and unloading. This implicates
titin's C-terminal PEVK region in regulating passive and active muscle mechanics and muscle plasticity.