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Mechanical stresses govern myoblast fusion and myotube growth

Yoann Le Toquin, Sushil Dubey, Aleksandra Ardaševa, Lakshmi Balasubramaniam, Emilie Delaune, Valérie Morin, Amin Doostmohammadi, Christophe Marcelle, Benoît Ladoux

Posted on: 29 January 2025 , updated on: 30 January 2025

Preprint posted on 23 November 2024

Muscles in Motion: How Stressful Dance Floors Turn Cells into Synchronized Superstars.

Selected by Vibha SINGH, Prasanna Padmanaban

Categories: cell biology

Background and hypothesis.

Myogenesis, the formation of multinucleated myofibers (myotubes), relies on a critical event: myoblast fusion. Imagine building a dance crew where each dancer (your muscle cells, called myoblasts) needs to join hands and form a perfect line (myotube) for the big finale. But here’s the catch: they can only line up and connect at specific spots on the dance floor where the “dance floor pressure” is just right. This study by Yoann Le Toquin et al. reveals that these special spots, like dance floor hotspots, are areas of stress where the cells feel the push and pull of their environment. These stress points act like invitations for the dancers to come together and perform their fusion act. The floor (extracellular matrix: a supportive structure outside the cells) even adjusts to guide the dancers into formation (Figure 1A).

In short, muscle cells don’t just randomly join forces—they are guided by the rhythm of mechanical pressures, ensuring a smooth and well-organized performance that makes muscle growth possible!

 

 

Figure 1: (A) Cartoon depiction of the study, highlights the role of stresses for perfect myoblast fusion (generated using ChatGPT 4). (B) Reproduced from Figure 2B. Snapshots of the evolution of the myoblast culture transduced with the lentiviral construct allowing to observe actin (green) and myosin-II (red) cytoskeleton along a 48h period. Close-ups on areas showing fusion events during the time-lapse. White arrowheads indicate the site of fusion characterized by an actin focus preceding cytoskeletal merging and fluorescence mixing.

 

Although crucial key molecules are well-known, the regulation by the mechanical framework remains unclear in regulating myotube formation. How mechanical tension impacts sarcomeric assembly is well studied, but the precise role of mechanical forces in myoblast fusion and patterning has not been fully explored. Understanding these forces is crucial for decrypting tissue architecture and function. Authors of the preprint demonstrate that myoblast fusion can be explained through active nematics (denoting a state of a liquid crystal in which the molecules are oriented in parallel), where the arrangement of the molecules is linear (Figure 1B). Within this framework, cell behaviors and mechanical stresses govern events of fusion localization. The study also describe that topological defects generate regions of high compressive stress which eventually controls fusion, and the intensity of stress is enhanced as myoblasts differentiate into myotubes. The authors further develop a model connecting cell activity, stress, and ECM dynamics during this process.

Key findings

Muscle cells (myoblasts) don’t just randomly merge to form muscle fibers (myotubes). Instead, they rely on mechanical stresses in their environment to decide where and how to fuse. Think of it as these cells finding the perfect “dance floor hotspots” to come together and grow muscles efficiently.

(a) Observing the Dance Floor. The authors used advanced imaging techniques to track how myoblasts moved, aligned, and fused. They noticed that cells tend to gather and merge in specific areas of high mechanical stress and develop into self-organized domains during their transition to multinucleated myotubes.

(b) Testing the Environment. By manipulating the stiffness of the extracellular matrix (a supportive structure outside the cells) and applying controlled forces, they showed that these stresses directly influenced where fusion occurred. Softer or less stressed areas saw less activity—like a quiet corner of a dance floor. This underlines the importance of evolving mechanical stress in organizing fusion during differentiation.

(c) Topological Defects as Hotspots. Using mathematical models and experiments, they found that cells align in patterns resembling liquid crystals. Fusion happens most actively at special points in these patterns, called topological defects, which are like hotspots for mechanical stress. Comet-shaped (+1/2) and trefoil-like (−1/2) topological defects develop, typical of active nematic systems, driving collective cell organization. This nematic behavior is regulated by actin organization, and inhibition of myosin-II damages the order, which increases defect density. This emphasizes the role of cytoskeleton maturation in self-organization and myoblast fusion.

(d) Looking at the Bigger Picture. The extracellular matrix itself seemed to guide this process. It adjusts and organizes along with the cells, creating an environment where the fusion process can thrive. Further, modelling results discloses defect stabilization, reduce motion, amplify stress intensity, and organize stress patterns over time.

What do we like most about the preprint?

Previous studies focused on biochemical signals driving myoblast fusion. This study shifts the spotlight to mechanical stresses, showing how physical forces organize cell alignment and fusion. The discovery that myoblasts align in liquid crystal-like patterns, with fusion occurring at topological defects (areas of high stress), is a novel and intriguing concept. It’s like uncovering hidden “fusion zones” on the cellular map. The extracellular matrix (ECM) isn’t just a passive structure—it actively participates, aligning and adapting to mechanical forces to guide myoblasts. We like how the authors have successfully assimilated active nematic principles to disclose the link between topological defects and myoblast fusion, offering a novel perspective on the role of mechanics in myogenesis. This two-way interaction between cells and their environment was previously underappreciated.

Significance of the study

Understanding how mechanical stresses guide muscle cell fusion gives us insights into muscle development, tissue repair and formation, and diseases associated with their dysfunction.  It could lead to better treatments for muscle-related conditions or improved strategies for tissue engineering. In simple terms, this study shows that building muscles is not just about having the right cells—it’s about creating the perfect environment for them to come together and grow!

Open Questions

1)     Does the long-term stability of myotube structures get affected by the mechanical feedback loop between cell-generated forces and ECM reorganization?

2)     Do you think the alignment of myoblasts into liquid crystal-like patterns and their fusion at topological defects has evolutionary significance? Could it be a conserved mechanism across species?

3)     Was it surprising to find such precise hotspots for fusion at topological defects? Did you observe any variations in these patterns depending on matrix stiffness or external force?

4)     If you were to design a therapeutic approach targeting mechanical stress, what aspect would you prioritize: enhancing ECM adaptability, tuning cellular response, or both?

5)     Did you notice differences in how individual myoblasts responded to mechanical stress, such as variability in their ability to sense or adapt to stress?

Tags: biomechanics, ecm, myoblast fusion

doi: https://doi.org/10.1242/prelights.39556

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