Mechanosensitive channel gating in dystrophic muscle: force partitioning and the calcium hypothesis of muscular dystrophy

This is the authors' abstract. We don't add key points for this paper.

The calcium hypothesis of muscular dystrophy links dystrophin deficiency to abnormal Ca² + handling and Ca² + -dependent muscle injury, but several interacting processes can contribute to the abnormal Ca² + load. These include membrane lesions, constitutive channel activity, mechanically regulated Ca² + entry, and altered sarcoplasmic reticulum release. Single-channel recordings from dystrophin-deficient muscle demonstrate increased resting activity, altered pressure responses, stretch-inactivated behavior, and changes in subconductance occupancy. Utrophin depletion on the mdx background further modifies channel gating. This review develops force partitioning as a framework for interpreting these observations: cytoskeletal and matrix attachments, membrane reservoirs, and the local lipid environment determine how an applied load reaches a channel and changes its gating free energy. Bilayer tension is sufficient to activate several established mechanosensitive channels, but this does not exclude tether-mediated or indirect activation in native tissue. The framework distinguishes measured phenotypes from proposed mechanisms and explicitly separates force-controlled from displacement-controlled loading. It also treats pipette pressure as a stimulus rather than a direct measure of membrane tension. An illustrative calculation shows how increased resting activity can coexist with a rightward pressure–response shift, although the relevant patch geometry has not been established in dystrophin/utrophin double-knockout fibers. The resulting predictions concern local mechanics, channel-state occupancy, Ca² + handling, and structural rescue. Force partitioning therefore provides a testable contribution to the calcium hypothesis, not a uniquely established explanation of all dystrophic channel phenotypes.