Plakoglobin supports length-dependent force generation and cardiac resistance to fasting

Mechanical activity protects muscle from atrophy, but how contractile forces relate to anabolic signaling remains unclear. We previously showed that plakoglobin promotes insulin-PI3K-AKT-FoxO signaling and that its loss causes skeletal muscle atrophy. Here, super-resolution microscopy revealed that plakoglobin localizes with desmin at the sarcolemma and is lost from the membrane during fasting-induced skeletal muscle atrophy. In skinned muscle fibers, plakoglobin downregulation impaired stretch-induced increase in myofilament activation at long sarcomere length. During fasting, skeletal muscle lost sarcolemmal plakoglobin-containing complexes, insulin signaling, and mass and induced MuRF1 and MAFbx/Atrogin1. In contrast, cardiac muscle retained these complexes and anabolic signaling, and maintained its mass. Cardiac plakoglobin also resisted AAV-shJUP-mediated depletion despite viral delivery. Moreover, MEK inhibition disrupted this cardiac response, reduced AKT signaling, induced atrogenes, and decreased cardiac mass. Thus, plakoglobin supports force generation at increased sarcomere length, and preservation of plakoglobin-containing complexes and MEK-ERK signaling accompany cardiac resistance to fasting-induced atrophy.