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

Jerome Avellaneda, Clement Rodier, Fabrice Daian, Thomas Rival, Nuno Miguel Luis, Frank Schnorrer

Preprint posted on 18 July 2020

Article now published in Nature Communications at

Flying interconnected! The crosstalk between mitochondrial dynamics and skeletal muscle structure during Drosophila muscle morphogenesis.

Selected by Andrea Irazoki

Categories: cell biology, physiology


The skeletal muscle is one of the three types of muscles that comprise the muscular system, along with the cardiac and the smooth muscles. The main feature of muscles is their ability to contract either in a voluntary or involuntary manner. Muscle fibers, the cellular unit of skeletal muscles, are composed by myofibrils, which are in turn composed by sarcomeres, the functional unit of the muscle. These structures allow the mechanical process known as muscle contraction (Figure 1). Owing the high requirements of calcium ions and ATP during contraction, sarcomeres are surrounded by an extended mitochondrial network, which can be distributed in different shapes according to the skeletal muscle energetic and functional demands. Hence, histological structure of skeletal muscles, in terms of mitochondrial and myofibril architecture and interconnections, determines proper muscle development, as well as muscle metabolism and function. Here, Mishra et al. described the tight relationship between mitochondrial morphology and fiber typing in mice, being red oxidative muscle fibers, the ones that contain elongated mitochondria, whereas white glycolytic muscle fibers comprise short mitochondrial domains [2]. This study provided the first evidence showing that mitochondrial morphology, which is governed by mitochondrial dynamics, i.e. fusion and fission events, is essential for muscle fiber structure. In their preprint, Avellaneda et al. demonstrated that indirect flight muscles of flies, responsible for the movement of the wings (high power output with endurance), can convert towards a partially cross-striated muscle, which is a feature of body muscles like the abdomen or leg muscles. This muscle-type conversion associates with imbalances in mitochondrial dynamics during development, hereby, suggesting that the regulation of mitochondrial fusion and fission during myofibril morphogenesis can modulate the structure and hence, the function of the muscle.

Figure 1: Histological structure of skeletal muscles in Drosophila and in humans [1]. Each skeletal muscle is compartmentalized in muscle fascicles, which are in turn compartmentalized in muscle fibers, being muscle fibers the cellular unit of this organ. Muscle fibers are composed by myofibrils, which are in turn composed by sarcomeres, the functional unit of the muscle as these structures undergo the mechanical process known as muscle contraction.



First, the authors evaluated the impact of the developmental downregulation of the zinc-finger transcription factor Spalt, which is responsible for the formation of fibrillary flight muscle. The authors observed a transformation in the structure of myofibrils into cross-striated tubular morphology, as well as mitochondrial morphology changes to centrally concentrated mitochondria upon reduced Spalt expression levels. These evidences suggest that fibrillary flight muscle development associates with changes in mitochondrial morphology.

In order to provide a proof-of-concept of this hypothesis, the authors performed several functional assays, to promote either mitochondrial fragmentation or elongation during myofibril development of indirect flight muscles. On the one hand, mitochondrial fragmentation was induced by knocking down the fusion protein Marf or overexpressing the fission protein Drp1. These genetic modulations resulted in normal myofibril development and mitochondrial intercalation between myofibrils, despite of reduced mitochondria size. However, mitochondrial fragmentation during development resulted in impaired flight function. On the other hand, the induction of mitochondrial elongation was achieved by overexpressing Marf or the dominant negative form of Drp1, both of which caused decrease numbers of flight muscles. Besides, these muscles presented a transformation in their structure from fibrillary to cross-striated myofibril morphology, which resembles the myofiber morphology of leg muscles. This last piece of data was validated by analyzing the gene expression profile of markers associated with cross-striated myofibrils in Marf-overexpressing flight muscles. Besides, the authors observed that initiation of development of Marf-overexpressing flight muscles is comparable to wild-type muscles due to the fact that Spalt expression remain unchanged in both cases. This suggest that mitochondrial fusion determines myofibril structure downstream of Spalt (i.e. after initiation of flight muscle development).

Last but not least, time-course experiments revealed that during myofibril assembly and maturation, proper mitochondrial intercalation determines the growth and spacing of myofibrils. Therefore, imbalances in mitochondrial fusion and fission events have a strong impact in the resulting morphology of myofibrils. In summary, the main conclusion is that balanced mitochondrial dynamics during myofibril development allows proper mitochondrial network architecture and muscle transcriptional profile, resulting in the formation of either indirect flight muscles or body muscles, both of which undergo different metabolic reactions in order to fulfill their specific functions.



Until recently, the lack of evidence related to the crosstalk between intramuscular architecture and mitochondrial morphology has been a black hole in basic research focused on the metabolic impact of mitochondrial dynamics proteins in the muscle. In fact, many studies performed in mouse models where proteins involved in mitochondrial dynamics were constitutively ablated in skeletal muscles (see references [3-8], among others) have failed at properly understanding the nature of the resulting phenotypes due to the unknown roles of the ablated proteins during muscle development. For this reason, I think that the preprint of Avellaneda et al. provides beautiful data on this matter, shedding lights to a part of a whole research field that urgently seeks for further comprehension on the relationship between skeletal muscle structure and mitochondrial morphology.



  1. According to your data, the impact of imbalances in mitochondrial dynamics on myofibril assembly are downstream the effects of Spalt. Do you think that Spalt could regulate mitochondrial morphology? And if so, by which mechanism?
  2. You describe that by modulating mitochondrial dynamics during muscle development, indirect flight muscles can transform to partial cross-striated muscles. Have you observed similar effects in the opposite direction? In other words, can cross-striated muscles be converted into flight-like muscles by modulating their mitochondrial morphology?
The author is grateful to Dr Osvaldo Contreras (Victor Chang Cardiac Research Institute, Australia) for proofreading the highlight.


[1] Lemke S.B. and Schnorrer F. (2016) “Mechanical forces during muscle development” Mechanisms of Development 144(A): 92-101.

[2] Mishra P., Varuzhanyan G., Pham A.H. and Chan D.C. (2015) “Mitochondrial Dynamics is a Distinguishing Feature of Skeletal Muscle Fiber Types and Regulates Organellar Compartmentalization” Cell Metabolism 22, 1033-1044.

[3] Tezze C., et al (2017) “Age-Associated Loss of Opa2 In Muscle Impacts Muscle Mass, Metabolic Homeostasis, Systemic Inflammation and Epithelial Senescence” Cell Metabolism 25(6): 1374-1389.

[4] Rodriguez-Nuevo A., et al (2018) “Mitochondrial DNA ant TLR9 Drive Muscle Inflammation upon Opa1 Deficiency” EMBO Journal 37(10)e96553.

[5] Dulac M., et al (2020) “Drp1 Knockdown Induces Severe Muscle Atrophy and Remodelling, Mitochondrial Dysfunction, Autophagy Impairment and Denervation” The Journal of Physiology 598(17): 3691-3710.

[6] Romanello V., et al (2019) “Inhibition of the Fission Machinery Mitigates Opa1 Impairment in Adult Skeletal Muscles” Cells 8(6): 597.

[7] Sebastian D., et al (2016) “Mfn2 Deficiency Links Age-related Sarcopenia and Impaired Autophagy to Activation of an Adaptive Mitophagy Pathway” EMBO Journal 35(15)1677-93

[8] Zhang Z., Sliter D.A., Bleck C.K.E., and Ding S. (2019) “Fis1 Deficiency Differentially Affect Mitochondrial Quality in Skeletal Muscle” Mitochondrion 49:217-226


Posted on: 4 September 2020 , updated on: 24 September 2020


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Author's response

Frank Schnorrer, Nuno Luis and Jerome Avellaneda shared

  1. According to your data, the impact of imbalances in mitochondrial dynamics on myofibril assembly are downstream the effects of Spalt. Do you think that Spalt could regulate mitochondrial morphology? And if so, by which mechanism?

Spalt is definitely at the top of the hierarchy determining myofibril (we knew that from Schönbauer et al., Nature 2011) and mitochondrial morphology (our new study). Spalt thus controls the muscle type specific aspects of mitochondrial morphology. It could do so directly by regulating mitochondrial protein expression (evidence in Spletter et al., EMBOR 2014) or indirectly by the regulating sarcomeric protein expression, followed by the mechanical feedback between mitochondria and myofibrils that we suggest here. This feedback may go in both directions between myofibrils and mitochondria.


  1. You describe that by modulating mitochondrial dynamics during muscle development, indirect flight muscles can transform to partial cross-striated muscles. Have you observed similar effects in the opposite direction? In other words, can cross-striated muscles be converted into flight-like muscles by modulating their mitochondrial morphology?

This is an interesting point. We can indeed transform cross-striated leg muscles to fibrillar flight muscles. However, thus far only by ectopically expressing Spalt in developing leg muscle, in which it is normally not present (Schönbauer et al., Nature 2011). By modulating mitochondrial dynamics we have thus far not yet been able to achieve a similar transformation of the myofibril morphology. That said, very drastic modulation of mitochondrial dynamics can result in lethality. Thus, we need to time the modulations precisely to be able to observe the morphology of an adult leg muscle. A project for the future.

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