Anisotropic mechanosensitive pathways in the diaphragm and their implications in muscular dystrophies

Abstract

The diaphragm is the "respiratory pump;" the muscle that generates pressure to allow ventilation. Diaphragm muscles play a vital function and thus are subjected to continuous mechanical loading. One of its peculiarities is the ability to generate distinct mechanical and biochemical responses depending on the direction through which the mechanical forces applied to it. Contractile forces originated from its contractile components are transmitted to other structural components of its muscle fibers and the surrounding connective tissue. The anisotropic mechanical properties of the diaphragm are translated into biochemical signals that are directionally mechanosensitive by mechanisms that appear to be unique to this muscle. Here, we reviewed the current state of knowledge on the biochemical pathways regulated by mechanical signals emphasizing their anisotropic behavior in the normal diaphragm and analyzed how they are affected in muscular dystrophies.

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“…Indeed, compared to other muscles such as the biceps femoris, when the diaphragm muscle has been exposed to longitudinal, and later transverse load (mechanical stretch), the latter has increased passive tension, suggesting an "easier" extensibility in the longitudinal direction (along the muscle fibers) compared to transverse [80]. Therefore, the experiments on mutant mice null proteins responsible for mechanical properties has allowed for a deeper understanding of the role of extra-myofilament cytoskeletal structures that are part of the costamers such as desmin-, integrins-, and the dystrophin-associated glycoprotein complex (Figure 3).…”

“…The authors predicted the diaphragm muscle mechanical behavior through finite element model (FEM) simulation and described alterations in the mechanical properties as age-and disease-dependent [85]. Pardo and co-workers [80] reviewed the biochemical pathways involved in remodeling of diaphragm mechanical properties, describing the importance of alterations of diaphragm mechanical properties also in terms of mechanotransduction disruption or abnormalities, and its consequences on respiratory functions. These studies are all important in enhancing our understanding of pathogenic changes to the mechanical properties of the diaphragm.…”