Along with its well-documented role as a track for cargo transport, the microtubule (MT) cytoskeleton is linked to diverse structural and signaling roles in the cardiac myocyte. MTs can facilitate the rapid transmission of mechanical signals to intracellular effectors, a process termed mechanotransduction. A proliferated MT network may also provide a mechanical resistance to cardiac contraction in certain disease states. Yet our understanding of how MTs resist compression and transmit mechanical signals has been impaired by a lack of direct observation and by the unpredictable effects of blunt pharmacological tools.

Direct observation of MT mechanical behavior during contraction is the most straightforward way to elucidate the mechanisms underlying MT contributions to heart function. Advances in imaging have made this possible at temporal and spatial resolutions that permit quantification of MT geometry during the contraction cycle. Furthermore, recent evidence suggests that posttranslational modification of the microtubule network, specifically “detyrosination,” regulates cardiac mechano-transduction. This raises the question of whether detyrosination alters how microtubules respond to the changing mechanical loads inherent to each cardiac cycle. To answer these questions, we used advanced imaging techniques to explore MT behavior in beating murine cardiomyocytes.

During contraction, MTs must somehow accommodate the changing geometry of the myocyte. In a typical myocyte, this was accomplished by deforming into a sinusoidal buckled configuration that returned to an identical resting configuration after each beat. The periodic nature of these buckles coincided with the repeating contractile units of the cardiomyocyte known as sarcomeres, which suggested a direct interaction. Desmin intermediate filaments were identified as a key component of an anchoring complex that links MTs to the sarcomere and imparts structural organization to the MT network.

The physical link between microtubules and the sarcomere was highly dependent on detyrosination. In myocytes where detyrosination was suppressed, MTs often accommodated the contraction by sliding past each other rather than buckling as the sarcomere shortened. Disrupting the MT-sarcomere interaction allowed the sarcomere to shorten farther and faster, as well as decreased overall stiffness. Conversely, promoting detyrosination was sufficient to increase myocyte stiffness and impede the contraction of the myocyte. Consistently, clinical data showed a direct correlation between excess detyrosination and functional decline in patients with hypertrophic cardiomyopathy.

Thus, microtubules can provide mechanical resistance to the myocyte through interactions with the sarcomere, forming load-bearing spring elements in parallel with the contractile apparatus. These interactions are mediated by a detyrosination-dependent association with desmin that regulates myocyte stiffness and contractility. Excess detyrosination promotes the interaction between MTs and the sarcomere, which increases resistance to contraction and may contribute to reductions in cardiac function in certain disease states.

When a cardiomyocyte (A) is compressed (B), as occurs during systolic contraction, MTs buckle under load. In a typical myocyte (C), detyrosinated MTs are mechanically coupled to the sarcomere and buckle during contraction (D). When detyrosination is reduced (E), this interaction is disrupted and MTs buckle less, which allows sarcomeres to shorten and stretch with less resistance.