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Molecular and cellular basis of genetically inherited skeletal muscle disorders

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From Nature Reviews Molecular Cell Biology

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Abstract

Neuromuscular disorders comprise a diverse group of human inborn diseases that arise from defects in the structure and/or function of the muscle tissue — encompassing the muscle cells (myofibres) themselves and their extracellular matrix — or muscle fibre innervation. Since the identification in 1987 of the first genetic lesion associated with a neuromuscular disorder — mutations in dystrophin as an underlying cause of Duchenne muscular dystrophy — the field has made tremendous progress in understanding the genetic basis of these diseases, with pathogenic variants in more than 500 genes now identified as underlying causes of neuromuscular disorders. The subset of neuromuscular disorders that affect skeletal muscle are referred to as myopathies or muscular dystrophies, and are due to variants in genes encoding muscle proteins. Many of these proteins provide structural stability to the myofibres or function in regulating sarcolemmal integrity, whereas others are involved in protein turnover, intracellular trafficking, calcium handling and electrical excitability — processes that ensure myofibre resistance to stress and their primary activity in muscle contraction. In this Review, we discuss how defects in muscle proteins give rise to muscle dysfunction, and ultimately to disease, with a focus on pathologies that are most common, best understood and that provide the most insight into muscle biology.

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Fig. 1: Schematic of the costamere and diseases linked to the dystrophin glycoprotein complex.
Fig. 2: Sarcomere structure in skeletal muscle and its dysfunction in diseases.
Fig. 3: Proteins linked to the nuclear envelope and their association with muscle diseases.
Fig. 4: Excitation–contraction coupling at the triad and its dysfunction.
Fig. 5: Skeletal muscle membrane repair.
Fig. 6: Factors linked to protein turnover and quality control in the muscle and their links to disease.

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Acknowledgements

The authors acknowledge their colleagues and laboratory members who provided important feedback on this Review including R. Crosbie, J. Chamberlain, E. McNally and A. Demonbreun.

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Authors and Affiliations

  1. Departments of Paediatrics and Molecular Genetics, University of Toronto, Toronto, Ontario, Canada

    James J. Dowling

  2. Division of Neurology and Program for Genetics and Genome Biology, The Hospital for Sick Children Peter Gilgan Centre for Research and Learning (PGCRL), Toronto, Ontario, Canada

    James J. Dowling

  3. Department of Neurology, Washington University School of Medicine, St Louis, MO, USA

    Conrad C. Weihl

  4. Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA

    Melissa J. Spencer

Authors
  1. James J. Dowling
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  2. Conrad C. Weihl
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  3. Melissa J. Spencer
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The authors contributed equally to all aspects of the article.

Corresponding author

Correspondence to Melissa J. Spencer.

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Competing interests

M.J.S. is a co-founder of a startup called Myogene Bio. M.J.S. and C.C.W. serve on the Research Advisory Board for the Muscular Dystrophy Association. J.M.D. is the Chief Medical Officer for Deep Genomics

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Glossary

Reticular lamina

One of the layers of the basement membrane, composed of collagens I, III and VI.

Ambulation

The ability to walk, unassisted.

Repeat expansions

Duplication of untranslated regions of the genome.

Myotonic dystrophy

Multi-system disorders with the feature of an inability of muscles to relax after contraction.

Fascioscapulohumeral dystrophy

Group of disorders due to failed regulation of the developmental protein DUX4.

Syntrophins

Adapter proteins linked to the cytoskeleton.

GRB2

Adapter protein often involved in coupling downstream signalling to cytoskeletal proteins.

Becker muscular dystrophy

(BMD). Disease that is allelic with Duchenne muscular dystrophy (DMD). BMD mutations are usually in-frame deletions and the phenotype is milder than in DMD.

Mdx mouse model

Murine model of Duchenne muscular dystrophy containing a premature termination codon in exon 23 of the Dmd gene.

Walker–Warburg syndrome

Congenital muscle disorders manifesting as muscle weakness and eye and brain abnormalities.

Muscle–eye–brain disease

Group of congenital muscle diseases that also impact the eye and brain, and are caused by abnormal glycosylation of α-dystroglycan.

Bethlem myopathy

Diseases due to mutations in collagen genes that result in defects in muscle and connective tissue.

Ullrich myopathy

Congenital muscle disorders due to mutations in genes encoding collagen VI.

Type 1 fibres

Muscle fibres that are slow to fatigue and rely on oxidative metabolism.

Arthrogryposis

Conditions involving multiple joint contractures.

Type 2 fibres

Muscle fibres that are quick to fatigue and rely on glycolytic metabolism.

Kelch domain

A protein motif found in Kelch proteins, which are adapters for cullin–E3 ubiquitin ligases.

Laing distal myopathy

Muscle disease due to mutations in MYH7 that causes late onset of muscle weakness, initiating in distal muscles.

Myosin storage myopathy

A non-progressive muscle disorder involving excessive accumulation of myosin.

Centronuclear myopathy

Group of muscle disorders that demonstrate the specific appearance of small, centrally nucleated muscle fibres on a muscle biopsy sample.

Cores

Structures on a muscle biopsy sample that lack NADH or SDH staining.

Emery–Dreifuss muscular dystrophy

A group of muscle diseases linked to mutations in either FHL1, EMD or LMNA.

Central core disease

Group of muscle disorders that demonstrate lack of histochemical staining as small holes or ‘cores’ on muscle biopsy samples.

Minicore myopathy

Muscle disorders that show small holes or ‘minicores’ on muscle biopsy samples.

Congenital fibre type disproportion

Muscle diseases that show altered distribution of type 1 or type 2 muscle fibres.

Malignant hyperthermia

A condition in which excessive calcium is released from the ryanodine receptor, leading to severe spasms and increased heart rate.

Exertional rhabdomyolysis

Muscle tissue breakdown that occurs after heavy muscle use.

SERCA

A P-type calcium ATPase that pumps calcium back into the sarcoplasmic reticulum following relaxation after muscle contraction.

Calcium calmodulin kinase II

(CaMKII). Kinase that is activated by calcium–calmodulin, which in the muscle has been shown to promote type 1 fibre gene expression for muscle adaptation to exercise.

Aldolase

An enzyme, also known as fructose bisphosphate aldolase A, that catalyses the fourth step of glycolysis.

Store-operated calcium entry

A process that triggers calcium entry from the extracellular space in response to depletion of intracellular calcium stores.

Tubular aggregate myopathy

Muscle disease with appearance of tubular aggregates on biopsy samples.

Stormorken syndrome

A rare condition associated with tubular aggregate myopathy in which many tissues are affected.

Phosphatidylserine

A phospholipid that is present in the sarcolemmal membrane on the cytoplasmic leaflet.

Synaptotagmin

A C2-domain-containing (Ca2+ sensing) protein that is typically involved in membrane trafficking.

EHD proteins

A family of proteins containing the epidermal growth factor receptor pathway substrate 15 homology domain that are typically involved in cellular trafficking.

Myoshi myopathy

A muscle disorder due to mutations in the DYSF gene. This disease is allelic with limb girdle muscular dystrophy type 2B, but manifests with primarily distal muscle involvement.

Vici syndrome

Developmental disorder that involves skeletal muscle, heart and other organ systems.

Danon disease

Lysosomal storage disorder due to mutations in LAMP2.

Pompe disease

Lysosomal storage disorder affecting skeletal muscle and heart, related to aberrant glycogen accumulation.

X-linked myopathy with excessive autophagy

Childhood muscle disorder involving proximal muscle weakness due to disruption of an unidentified gene on the X chromosome.

Sarcotubular myopathy

A muscle disorder demonstrating membrane-enclosed vacuoles; allelic with limb girdle muscular dystrophy type 2H due to mutations in TRIM32.

Bardet–Biedl syndrome

A group of rare disorders affecting multiple organs.

Marinesco–Sjögren syndrome

A multi-organ disease involving muscle weakness, ataxia and cataracts.

Selenocysteine protein family

Proteins containing one or more selenocysteines, which are amino acids that use selenium instead of sulfur in cysteine.

Mallory body myopathy

Inclusions on a muscle biopsy sample that stain positively for desmin.

Exon skipping

Therapeutic strategy to restore the reading frame of a gene.

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Dowling, J.J., Weihl, C.C. & Spencer, M.J. Molecular and cellular basis of genetically inherited skeletal muscle disorders. Nat Rev Mol Cell Biol 22, 713–732 (2021). https://doi.org/10.1038/s41580-021-00389-z

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