Myofibril and mitochondria morphogenesis are coordinated by a mechanical feedback mechanism in muscle

Abstract

Complex animals build specialised muscle to match specific biomechanical and energetic needs. Hence, composition and architecture of sarcomeres as well as mitochondria are muscle type specific. However, mechanisms coordinating mitochondria with sarcomere morphogenesis are elusive. Here we use Drosophila muscles to demonstrate that myofibril and mitochondria morphogenesis are intimately linked. In flight muscles, the muscle selector spalt instructs mitochondria to intercalate between myofibrils, which in turn mechanically constrain mitochondria into elongated shapes. Conversely in cross-striated muscles, mitochondria networks surround myofibril bundles, contacting myofibrils only with thin extensions. To investigate the mechanism causing these differences, we manipulated mitochondrial dynamics and found that increased mitochondrial fusion during myofibril assembly prevents mitochondrial intercalation in flight muscles. Strikingly, this coincides with the expression of cross-striated muscle specific sarcomeric proteins. Consequently, flight muscle myofibrils convert towards a partially cross-striated architecture. Together, these data suggest a biomechanical feedback mechanism downstream of spalt synchronizing mitochondria with myofibril morphogenesis.

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

“…During the stage of myofibril assembly, the mitochondria morphology changes and the expression of mitochondrial genes increase (Avellaneda et al, 2020;. Consistently, we found an induction of mitochondria dynamics and protein import regulators (Opa1, Tom40) in hippo-IR and yorkie-CA myofibers at 32 h APF as well as a consistent up-regulation of mRNAs coding for respiratory chain components, including the F1F0 ATP synthase complex (complex V) subunit blw, the NADH dehydrogenase (ubiquinone) subunit ND-75 and the Ubiquinol-cytochrome c reductase subunit UQCR-C2, which are all required to boost ATP production during muscle fiber growth ( Figure 8A,B, Supplementary File 2).…”

“…In Drosophila indirect flight muscles, transcription of sarcomeric and mitochondrial protein coding genes starts just before myofibril assembly and is then strongly boosted during myofibril maturation, when myofibrils grow in length and width (González-Morales et al, 2019;Shwartz et al, 2016;Spletter et al, 2018). Concomitantly with the growth of the myofibrils, the T-tubule network forms (Peterson and Krasnow, 2014;Sauerwald et al, 2019) and also the mitochondria grow in size (Avellaneda et al, 2020;Spletter et al, 2018). How this precise transcriptional control is achieved and coordinated with muscle fiber growth is unclear.…”

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

“…During the stage of myofibril assembly, the mitochondria morphology changes and the expression of mitochondrial genes increase (Avellaneda et al, 2020;. Consistently, we found an induction of mitochondria dynamics and protein import regulators (Opa1, Tom40) in hippo-IR and yorkie-CA myofibers at 32 h APF as well as a consistent up-regulation of mRNAs coding for respiratory chain components, including the F1F0 ATP synthase complex (complex V) subunit blw, the NADH dehydrogenase (ubiquinone) subunit ND-75 and the Ubiquinol-cytochrome c reductase subunit UQCR-C2, which are all required to boost ATP production during muscle fiber growth ( Figure 7A,B, Supplementary Table 2).…”

“…Concomitantly with the growth of the myofibrils, also the mitochondria grow in size (Avellaneda et al, 2020). How this precise transcriptional control is achieved and coordinated with muscle fiber growth is unclear.…”

An Evolutionarily Conserved Regulatory Pathway of Muscle Mitochondrial Network Organization

“…Here, we take advantage of the natural energetic and contractile differences 19, 20 among muscle types within the genetically tractable fruit fly, Drosophila melanogaster , together with the known Drosophila muscle type specification factor, spalt major ( salm ) 21, 22 to identify an evolutionarily conserved regulatory pathway of muscle mitochondrial network organization. By performing a proteomic screen on muscles with five different combinations of contractile type, mitochondrial network type, and Salm expression level, we identified 142 proteins associated with muscle fiber type.…”