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When muscles (green) and tendons (red) are under tension, regular myofibrils assemble, with their sarcomeric units arrayed like pearls on a string (on the right in green).
Image credit: Manuela Weitkunat © MPI of Biochemistry
Tension triggers muscle building
Scientists at the Max Planck Institute (MPI) of Biochemistry in Munich-Martinsried (Germany) recently identified a key mechanism involved in building basic muscle architecture during embryo development.
Skeletal muscles are built from small contractile units called sarcomeres. Many of these sarcomeres are connected in well-ordered series to form myofibrils, spanning from the end of one muscle to the other. Contractions of the sarcomeres therefore result in contraction of the entire muscle.
“Mechanical tension is the essential trigger. If tension is eliminated, not regular myofibrils, but only short, random protein assemblies can form. Such muscles are non-functional.”
Frank Schnorrer, head of Muscle Dynamics group, Max Planck Institute, Germany.
Research results are published in the journal Current Biology.
In order to move the body, skeletal muscles pull on the skeleton. For efficient muscle and skeletal movements, it is essential that the muscle contracts only along one defined axis, for example leg muscles along the femur of the thigh. Directed contractions are achieved by myofibrils that span the entire length of the muscles of the femur. At either end of the muscle, myofibrils are anchored to tendon cells, which themselves are linked to the skeleton. “Therefore, the entire tensil force is transfered from the muscle to the skeleton,” explains Frank Schnorrer.
But, how are so many hundreds of sarcomeres and long myofibrils built along a defined axis during muscle development?
PhD student Manuela Weitkunat and PostDoc Aynur Kaya-Çopur investigated this question in the fruit fly, Drosophila melanogaster. They discovered that shortly after the Drosophila flight muscles contract tendons, mechanical tension occurs. This tension builds up just before sarcomeres are formed, reaching through the entire muscle-tendon-skeleton system. Now, a tension axis exists along the entire muscle, and positional information along the muscle tells the sarcomeres in which direction they must form.
Absence of tension results in chaos
By manipulating genetic mutations in the fly, scientists at the Muscle Dynamics group were able to block the attachment of flight muscles to tendons therefore eliminating tension formation in the system. As a consequence, muscles could not build long ordered myofibrils and instead distributed the sarcomeric protein complexes in a chaotic way.
In order to directly test the influence of mechanical tension, the scientists used a laser to cut the tendons off the muscle. This strategy to release any form of tension led to a major defect in sarcomere and myofibril formation.
“Based on these results, we are suggesting a new model of myofibril formation, which proposes tension dependent self-assembly of the sarcomeric components.
“When a certain tension threshold is reached, myofibril formation is triggered. If tension is compromised, the sarcomeric components have no spatial information and assemble chaotically.”
As human muscles also contain myofibrils that are built by periodically arrayed sarcomeres, it is most likely that a similar tension-based assembly model also applies during human muscle development.
Muscle-tendon attachment results in tension buildup
Tension buildup is followed by simultaneous myofibrillogenesis in muscle
Tension is required to trigger myofibrillogenesis
Higher animals generate an elaborate muscle-tendon network to perform their movements. To build a functional network, developing muscles must establish stable connections with tendons and assemble their contractile apparatuses. Current myofibril assembly models do not consider the impact of muscle-tendon attachment on myofibrillogenesis. However, if attachment and myofibrillogenesis are not properly coordinated, premature muscle contractions can destroy an unstable myotendinous system, leading to severe myopathies.
Here, we use Drosophila indirect flight muscles to investigate how muscle-tendon attachment and myofibrillogenesis are coordinated. We find that flight muscles first stably attach to tendons and then assemble their myofibrils. Interestingly, this myofibril assembly is triggered simultaneously throughout the entire muscle, suggesting a self-assembly mechanism. By applying laser-cutting experiments, we show that muscle attachment coincides with an increase in mechanical tension before periodic myofibrils can be detected. We manipulated tension buildup within the myotendinous system either by genetically compromising attachment initiation and integrin recruitment to the myotendinous junction or by optically severing tendons from muscle. Both treatments cause strong myofibrillogenesis defects. We find that myosin motor activity is required for both tension formation and myofibril assembly, suggesting that myofibril assembly itself contributes to tension buildup.
Our results demonstrate that force-resistant attachment enables a stark tension increase in the myotendinous system. Subsequently, this tension increase triggers simultaneous myofibril self-assembly throughout the entire muscle fiber. As myofibril and sarcomeric architecture as well as their molecular components are evolutionarily conserved, we propose a similar tension-based mechanism to regulate myofibrillogenesis in vertebrates.
Manuela Weitkunat, Aynur Kaya-Çopur, Stephan W. Grill, Frank Schnorrer
M. Weitkunat, A. Kaya-Çopur, S.W. Grill and and F. Schnorrer: Tension and force-resistant attachment are essential for myofibrillogenesis in Drosophila flight muscle. Current Biology, March 13, 2014.