Titin-mediated control of cardiac myofibrillar function

Area of Science:

• Cardiovascular Physiology
• Muscle Mechanics
• Molecular Cardiology

Background:

• The Frank-Starling relationship describes increased ventricular pressure and stroke volume with end-diastolic volume.
• This regulation is largely governed by sarcomere length (SL)-dependent changes in cardiac myofibrillar force, loaded shortening, and power.
• Both cardiac myofibrillar force and absolute power decrease at shorter SL.

Purpose of the Study:

• To investigate the mechanism by which shorter SL enhances cardiac muscle power output when calcium-activated force levels are matched.
• To test the hypothesis that titin's compliance influences cross-bridge flexibility and power generation at different SLs.
• To determine the role of titin isoforms (N2B vs. N2BA) in SL-dependent power output.

Main Methods:

• Experiments were conducted on rat skinned cardiac myocytes.
• Sarcomere length (SL) dependence of power was measured at matched forces.
• Myocytes containing either N2B titin or the more compliant N2BA titin were utilized.

Main Results:

• When calcium-activated force levels were matched, shorter SL resulted in faster loaded shortening and greater peak normalized power output (PNPO).
• In myocytes with N2BA titin, PNPO was paradoxically less at short SL compared to long SL (ΔPNPO = -0.057 ± 0.049).
• In contrast, myocytes with N2B titin showed an increase in PNPO at short SL versus long SL (ΔPNPO = +0.012 ± 0.012).

Conclusions:

• Sarcomere length directly influences cross-bridge mechanical properties, mediated by titin.
• A more compliant titin (N2BA) does not support enhanced power at shorter SL when force is matched, suggesting titin's role in cross-bridge flexibility.
• This myofibrillar mechanism may sustain ventricular power during low preloads and its impairment could contribute to heart failure.