Biology subjects

Caremani, M.

Publications and source records attributed to Caremani, M..

3 recordsLinked to original sources

bioRxiv2024

An integrated picture of the structural pathways controlling the heart performance

Regulation of heart function is attributed to a dual filament mechanism: (i) the Ca2+-dependent structural changes in the regulatory proteins of the thin, actin-containing filament making actin available for myosin motor attachment1, and (ii) the release of motors from their folded (OFF) state on the surface of the thick filament2 allowing them to attach and pull the actin filament. Thick filament mechanosensing is thought to control the number of motors switching ON in relation to the systolic performance3, but its molecular basis is still unknown. Here high spatial resolution X-ray diffraction data from electrically paced rat trabeculae and papillary muscles call for a revision of the mechanosensing hypothesis and provide a molecular explanation of the modulation of heart performance also in light of the recent cryo-EM thick filament structure4, 5. We find that upon stimulation titin activation6 triggers structural changes in the thick filament that switch motors ON throughout the filament within [~][1/2] the maximum systolic force. These structural changes also drive MyBP-C N-terminus to bind actin7 promoting first motor attachments from the central 1/3 of the half-thick filament. Progression of attachments towards the periphery of half-thick filament with increase in systolic force is carried on by near-neighbour cooperative thin filament activation by attached motors8. The identification of the roles of MyBP-C, titin, thin and thick filaments in heart regulation enables their targeting for potential therapeutic interventions.

physiology↗

bioRxiv2021

Titin switches from an extensible spring to a mechanical rectifier upon muscle activation

In contracting striated muscle titin acts as a spring in parallel with the array of myosin motors in each half-sarcomere and could prevent the intrinsic instability of thousands of serially linked half-sarcomeres, if its stiffness, at physiological sarcomere lengths (SL), were ten times larger than reported. Here we define titin mechanical properties during tetanic stimulation of single fibres of frog muscle by suppressing myosin motor responses with Para-Nitro-Blebbistatin, which is able to freeze thick filament in the resting state. We discover that thin filament activation switches I-band titin spring from the large SL-dependent extensibility of the OFF-state to an ON-state in which titin acts as a SL-independent mechanical rectifier, allowing free shortening while opposing stretch with an effective stiffness 4 pN nm-1 per half-thick filament. In this way during contraction titin limits weak half-sarcomere elongation to a few % and, also, provides an efficient link for mechanosensing-based thick filament activation.

physiology↗

bioRxiv2018

A mechanical model of the half-sarcomere which includes the contribution of titin

The evidence, in both resting and active muscle, for the presence of an I-band spring element like titin that anchors the Z line to the end of the thick filament did not yet produce a proper theoretical treatment in a complete model of the half-sarcomere. The textbook model developed by A.F. Huxley and his collaborators in 1981, which provides that the half-sarcomere compliance is due to the contribution of the compliances of the thin and thick filaments and actin-attached myosin motors, predicts that at any sarcomere length the absence of attached motors results in an infinite half-sarcomere compliance, in contrast with the observations. Growing evidence for the presence of a titin-like I-band spring urges the 1981 model to be implemented to include the contribution of this element in the mechanical model of the half-sarcomere. The model described here represents a tool for the interpretation of measurements of half-sarcomere compliance at long sarcomere lengths and for investigations of the possible role of titin as the mechano-sensor in thick filament regulation.

biophysics↗