The Hippo pathway controls myofibril assembly and muscle fiber growth by regulating sarcomeric gene expression

Abstract

Skeletal muscles are composed of gigantic cells called muscle fibers, packed with force-producing myofibrils. During development, the size of individual muscle fibers must dramatically enlarge to match with skeletal growth. How muscle growth is coordinated with growth of the contractile apparatus is not understood. Here, we use the large Drosophila flight muscles to mechanistically decipher how muscle fiber growth is controlled. We find that regulated activity of core members of the Hippo pathway is required to support flight muscle growth. Interestingly, we identify Dlg5 and Slmap as regulators of the STRIPAK phosphatase, which negatively regulates Hippo to enable post-mitotic muscle growth. Mechanistically, we show that the Hippo pathway controls timing and levels of sarcomeric gene expression during development and thus regulates the key components that physically mediate muscle growth. Since Dlg5, STRIPAK and the Hippo pathway are conserved a similar mechanism may contribute to muscle or cardiomyocyte growth in humans.

An Analysis of Differentially Expressed Coding and Long Non-Coding RNAs in Multiple Models of Skeletal Muscle Atrophy

“…Interestingly, upregulated mRNAs under the four muscle atrophy conditions were related to the negative regulation of leukocyte activation and regulation of myotube differentiation pathways ( Figure 4C). These pathways include genes identified as negative (Cdkn1a and Ctsl) [25,26] and positive (Abcc8, Csrp3, Dlg5, Gdf5, Gpnmb, Il4ra, and Runx1) [27][28][29][30][31][32][33][34] regulators of muscle atrophy, supporting the validity of our analysis. Consistent with previous studies of each muscle atrophy condition [35][36][37][38][39], mRNAs with decreased expression in all muscle atrophy conditions were related to the terms of metabolism of carbohydrates and spermine metabolic processes ( Figure 4D).…”

A Candidate RNAi Screen Reveals Diverse RNA-Binding Protein Phenotypes in Drosophila Flight Muscle

“…After tendon attachment, sarcomeres and myofibrils self-assemble in the developing myofibers in a tension-dependent manner [2,56]. Spontaneous contractions during subsequent development help organize and refine sarcomere structure, and a coordinated shift in transcription promotes myofiber maturation [57][58][59][60]. This general process occurs in all muscles, but differential gene and splice isoform expression lead to distinct morphologies and biophysical properties among muscle fiber-types [6,7,61,62].…”

“…In severe cases, for example with knockdown of Sf3a2 with line 55650 (Sf3a2-55650) (Figure 3C), IFM myofibers were completely missing. A missing myofiber phenotype at 90h APF can result from defective myoblast migration or fusion or impaired tendon attachment [48,49], as well as defective regulation of cellular growth and tension [55,58,60], which suggests that RBP function is necessary for one or more of these cellular processes. We frequently observed detached or torn myofibers, for example in mbl-29585 (Figure 3D), CG9346-27013 (U2SURP) (Figure 3G), bru1-41586 (Figure 4E), and Rbfox1-27586 (Figure 3H).…”

Tension-driven multi-scale self-organisation in human iPSC-derived muscle fibers

“…Thus, tension may also feedback on the transcriptional machinery to boost expression of the sarcomeric components that are needed in large amounts to assemble myofibrils but are not present in stretching myotubes. Such a feedback mechanism has recently been suggested in developing flight muscles, which use the mechanosensitive Hippo/YAP pathway to boost sarcomere gene expression before and during myofibril morphogenesis [62]. Tension could also be sensed directly at the nuclear envelope, which is linked by the LINC complex to the actin cytoskeleton, inducing changes of nuclear shape and position during myofiber differentiation [63,64].…”