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Transcriptional mechanisms regulating skeletal muscle differentiation, growth and homeostasis

Nature Reviews Molecular Cell Biology volume 12, pages 349–361 (2011)Cite this article

Subjects

Key Points

  • The requirement for locomotion led to the evolution of muscles in all animal phyla.

  • The determination and terminal differentiation of muscle cells is governed by four transcription factors known as myogenic regulatory factors (MRFs): myogenic factor 5 (MYF5), muscle-specific regulatory factor 4 (MRF4), myoblast determination protein (MYOD) and myogenin.

  • Upstream of these are other transcription factors; for example, paired box proteins, T-box transcription factors and sine oculis homeobox (SIX) proteins, which either prepare the stage for MRFs to initiate myogenesis or activate MRFs.

  • Myogenesis is also regulated post-transcriptionally by the action of microRNAs, which are thought to regulate the transcription factors that control myogenesis.

  • Muscles can be remodelled postnatally to switch between fibre types (slow-twitch and fast-twitch) to adapt to specific conditions. The type of neuronal activity acting on a fibre is probably the most important factor determining fibre type.

  • Muscle remodelling can also affect muscle mass; this is regulated by anabolic and catabolic signalling pathways, which induce muscle hypertrophy and muscle atrophy, respectively. Mechanical stress and hormones also feed into these signalling pathways.

  • Some of the factors involved in early muscle development, such as SIX proteins and myogenin, also have roles in postnatal changes of muscle phenotype and mass.

Abstract

Skeletal muscle is the dominant organ system in locomotion and energy metabolism. Postnatal muscle grows and adapts largely by remodelling pre-existing fibres, whereas embryonic muscle grows by the proliferation of myogenic cells. Recently, the genetic hierarchies of the myogenic transcription factors that control vertebrate muscle development — by myoblast proliferation, migration, fusion and functional adaptation into fast-twitch and slow-twitch fibres — have become clearer. The transcriptional mechanisms controlling postnatal hypertrophic growth, remodelling and functional differentiation redeploy myogenic factors in concert with serum response factor (SRF), JUNB and forkhead box protein O3A (FOXO3A). It has also emerged that there is extensive post-transcriptional regulation by microRNAs in development and postnatal remodelling.

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Figure 1: Striated muscle structure.
Figure 2: Different ways to activate the genetic programme of muscle differentiation.
Figure 3: Regulation of major myogenic pathways by microRNAs.
Figure 4: Control of postnatal muscle transcription and protein turnover.

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Acknowledgements

We acknowledge the contributions that have also advanced the field by those authors whose work we could not cite owing to space constraints. Work in the authors' laboratories was funded by: the UK Medical Research Council; the British Heart Foundation; The Excellence Cluster Cardio-Pulmonary System (ECCPS) of the Justus-Liebig-University, Giessen, Germany, the Goethe University, Frankfurt, Germany and the Max-Planck-Institute for Heart and Lung Research (DFG) Germany; and the University of Giessen and the University of Marburg Lung Center (UGMLC), funded by the government of the state of Hessen, Germany.

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Authors and Affiliations

  1. Department for Cardiac Development and Remodelling, Max-Planck-Institute for Heart and Lung Research, Benekestrasse 2, 61231, Bad Nauheim, Germany

    Thomas Braun

  2. Randall Division for Cell and Molecular Biophysics and Cardiovascular Division, King's College London, Muscle Signalling and Development Section, New Hunt's House, Guy's Campus, SE1 1UL, London, UK

    Mathias Gautel

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Glossary

Myofibril

The structural unit of striated muscle fibres, which is formed from longitudinally joined sarcomeres. Several myofibrils form each fibre.

Myoblasts

Embryonic cells that will become a muscle cell or part of a muscle cell.

Paraxial mesoderm

The mesodermal areas that form directly lateral to the neural tube.

Rostrocaudal axis

A description of anatomical location in animals. Rostral (from the latin rostrum meaning beak) refers to the anterior ('nose-end') of the animal and caudal (from the latin caudum meaning tail) refers to the posterior ('tail or feet end').

Somites

Mesodermal structures found on either side of the neural tube in vertebrate embryos that eventually give rise to muscle, skin and vertebrae.

Delamination

A process in embryology in which cells from a single layer separate to form two different layers, or laminae.

Neural crest

A group of embryonic cells that separate from the embryonic neural plate and migrate, giving rise to the spinal and autonomic ganglia, peripheral glia, chromaffin cells, melanocytes and some haematopoietic cells.

Hypaxial muscles

Muscles that usually lie ventral to the vertebrae and are innervated by the ventral ramus of the spinal nerves.

Epaxial muscles

Muscles that usually lie dorsal to the vertebrae (in fish and amphibiae they lie dorsal to the septum). They are innervated by the dorsal ramus of the spinal nerves.

Masseter muscles

A specific subset of branchiomeric muscles that are derived from the first branchial arch and are involved in mastication.

Pharyngeal muscle

A subgroup of head muscles acting on the pharynx to control swallowing.

Antagomirs

Synthetic or genetically engineered oligonucleotides used to silence endogenous microRNAs.

Soleus muscle

A muscle in the calf of the leg that flexes the ankle; in rodents it is predominantly composed of slow-twitch fibres.

Tibialis anterior muscle

A muscle in the front muscle compartment of the lower leg that helps to extend the ankle; in rodents it is predominantly composed of fast-twitch fibres.

Microgravity

Gravity below the 1Gal experienced on Earth; for example, during space flight.

Ubiquitin–proteasome system

A system of selective, ATP-dependent protein degradation, in which target proteins that have been conjugated by ubiquitin are degraded by the 26S proteasome. The ubiquitin conjugation step requires the activity of highly specific ubiquitin ligases.

Autophagy

A catabolic process involving the engulfment of (usually damaged) organelles and long-lived proteins or protein aggregates by double-membrane vesicles (autophagosomes) that fuse with lysosomes to form autolysosomes, in which their contents are degraded by acidic lysosomal hydrolases.

Cachexia

A syndrome of muscle loss that is usually caused by increased catabolic metabolism.

E3 ubiquitin ligases

A group of proteins that mediate the transfer of ubiquitin, often by linking the catalytic activity of an E2 transferase to recognition and binding of the specific substrates.

Sarcopenia

The degenerative loss of skeletal muscle mass and strength associated with ageing and pathological processes.

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Braun, T., Gautel, M. Transcriptional mechanisms regulating skeletal muscle differentiation, growth and homeostasis. Nat Rev Mol Cell Biol 12, 349–361 (2011). https://doi.org/10.1038/nrm3118

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