Myopathy Genetics and Muscle Cell Dynamics

Myopathies encompass a diverse group of muscle disorders defined by structural and functional defects in skeletal muscle fibres. Many congenital myopathies arise from inherited mutations in genes encoding proteins that regulate membrane trafficking, cytoskeletal architecture and excitation–contraction coupling. Within this spectrum, centronuclear myopathies (CNMs) illustrate how disruption of membrane remodelling proteins such as myotubularin (MTM1), dynamin-2 (DNM2) and amphiphysin-2 (BIN1) leads to mislocalisation of nuclei, defective triad assembly and impaired calcium handling. Emerging evidence has also implicated serine/threonine kinases, notably striated muscle preferentially expressed protein kinase (SPEG), in the maintenance of triad integrity and focal adhesion complexes. At the cellular level, precise biogenesis of transverse tubules, endosomal trafficking of ion channels and stabilisation of intermediate filaments underlie muscle fibre resilience during repeated contraction and stretch. Disruption of these dynamic processes can trigger maladaptive autophagy, mitochondrial mispositioning and altered cytoskeletal interactions, culminating in weakness and progressive loss of motor function. Advances in genetic screening have broadened diagnosis from neonatal to adult-onset forms, revealing genotype–phenotype correlations that guide prognosis and therapeutic design. Gene therapies, antisense oligonucleotides and small-molecule modulators are now being tailored to restore key proteins, modulate modifier genes and rebalance calcium homeostasis. This integration of genetics with muscle cell dynamics holds promise for personalised interventions across inherited and acquired myopathies.

Research from Nature Portfolio

Seminal studies have demonstrated that reducing DNM2 expression via antisense oligonucleotides in a mouse model of MTM1 deficiency prevents onset of muscle pathology and, when administered to symptomatic animals, reverses established histological and functional deficits within weeks. This work highlights DNM2 as a potent genetic modifier and offers a targeted strategy for restoring membrane remodelling and excitation–contraction coupling in centronuclear myopathy. In a complementary approach, hormone-based modulation using tamoxifen in murine myotubular myopathy has been shown to prolong survival and improve muscle strength. Rescue is mediated through oestrogen receptor signalling, leading to post-transcriptional downregulation of DNM2 and partial restoration of triad architecture. These findings underscore the translational potential of combining genetic and pharmacological interventions to correct muscle cell dynamics.

Myopathy Genetics and Muscle Cell Dynamics publication trend

The graph below shows the total number of articles in myopathy genetics and muscle cell dynamics across all publications each year (not limited to Nature Index journals).

Technical terms

Antisense oligonucleotide (ASO): A short, synthetic strand of nucleic acid designed to bind a specific mRNA and modulate its expression.

Triad: A specialised membrane junction in skeletal muscle consisting of a central transverse (T)-tubule flanked by two sarcoplasmic reticulum cisternae, essential for excitation–contraction coupling.

Excitation–contraction coupling: The physiological process by which an electrical stimulus at the muscle membrane triggers Ca2+ release from the sarcoplasmic reticulum, leading to contraction.

Dynamin-2 (DNM2): A GTPase involved in membrane fission and endocytic trafficking, mutations of which cause autosomal-dominant centronuclear myopathy.

Striated muscle preferentially expressed protein kinase (SPEG): A serine/threonine kinase that interacts with the myospryn complex to regulate triad stability and calcium homeostasis.

References

1. Loss of Mtm1 causes cholestatic liver disease in a model of X-linked myotubular myopathy. Journal of Clinical Investigation (2023).
2. Integrated multi‐omics approach reveals the role of striated muscle preferentially expressed protein kinase in skeletal muscle including its relationship with myospryn complex. Journal of Cachexia Sarcopenia and Muscle (2024).
3. Antisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice. Nature Communications (2017).
4. Tamoxifen therapy in a murine model of myotubular myopathy. Nature Communications (2018).
5. Loss of Myotubularin Function Results in T-Tubule Disorganization in Zebrafish and Human Myotubular Myopathy. PLOS Genetics (2009).
6. Myotubularin controls desmin intermediate filament architecture and mitochondrial dynamics in human and mouse skeletal muscle. Journal of Clinical Investigation (2010).
7. T-tubule biogenesis and triad formation in skeletal muscle and implication in human diseases. Skeletal Muscle (2011).
8. Pathogenic Mechanisms in Centronuclear Myopathies. Frontiers in Aging Neuroscience (2014).