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Review
. 2021 Nov;22(11):713-732.
doi: 10.1038/s41580-021-00389-z. Epub 2021 Jul 13.

Molecular and cellular basis of genetically inherited skeletal muscle disorders

James J Dowling  1   2 , Conrad C Weihl  3 , Melissa J Spencer  4
Affiliations
Review

Molecular and cellular basis of genetically inherited skeletal muscle disorders

James J Dowling et al. Nat Rev Mol Cell Biol. 2021 Nov.

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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Conflict of interest statement

Competing interests

1) MJS is a co-founder of a startup called Myogene Bio 2) MJS and CCW serve on the Research Advisory Board for the Muscular Dystrophy Association 3) JMD is the Chief Medical Officer for Deep Genomics

Figures

Figure 1:
Figure 1:. Schematic of the costamere and proteins linked to the dystrophin glycoprotein complex (DGC)
a| The terminal Z disc of the skeletal muscle sarcomere attaches to the membrane at the costamere, where it links to a large protein complex called the DGC. b| On the intracellular side of the membrane, the DGC links to the actin cytoskeleton, microtubules and intermediate filaments via dystrophin protein (aqua). Dystropin is a 427kDa protein comprised of an N-terminal actin binding domain (ABD), 4 hinges, 24 spectrin repeats, a cysteine rich (CR) region that attaches to beta dystroglycan, and a C terminus. Dystrophin is a scaffold for several other molecules including neuronal nitric oxide synthase (nNOS), which attaches vis syntrophin (SYN), as well as ankyrin and dystrobrevin. c| The DGC is made of two membrane-associated subcomplexes, the dystroglycan (DAG) complex and the sarcoglycan complex (consisting of α, β, γ, and δ sarcoglycans), linked together by sarcospan (SSPN). d| Alpha dystroglycan (α-DAG) is the extracellular-facing DGC member in the basal lamina of the ECM. It is an ECM receptor that interacts with laminin, primarily through O-linked glycans on its mucin domain. e| α-DAG also associates with other matrix molecules such as nidogen and perlecan that along with collagens IV and VI, connect the basal lamina to collagens I and III in the reticular lamina.
Figure 2 |
Figure 2 |. Schematic of a muscle cell and the proteins linked to the sarcomere Figure 2. Sarcomere structure in skeletal muscle.
a. Transmission electron micrograph of a longitudinal section of the sarcomere of zebrafish skeletal muscle. Z-disks are visible as electron-dense zig-zag vertical lines, M-band as a smooth dark line in the middle of the sarcomere, and the horizontal striations represent thick and thin filaments. The vacuolated areas are the triads, where excitation contraction coupling takes place. b. Schematic of the major protein components of the sarcomere. Thin filaments are composed of actin, nebulin, tropomyosin and the troponin complex with the following subunits: troponin T (TNNT, binds tropomyosin), troponin I (TNNI, binds actin), and troponin C (TNNC, binds the calcium ions). Thick filaments are composed of myosin and titin. Myosin consists of several domains: a head [two identical myosin heavy chains (MyHC), which bind actin], a neck [one pair of essential light chains (MyELC) and one pair of regulatory light chains (MyRLC)], and a tail. c. Schematic of a sarcomere in a relaxed state. d. Schematic of a sarcomere in contracted state. e. Schematic of a sarcomere during a defective contraction, which is a hallmark of thin-filament related nemaline myopathies. Mutations in nebulin (NEB) and actin (ACTA1) can lead to shorter thin filaments, defective actin assembly and dynamics, reduced force during muscle contraction, and lower sensitivity to calcium ions.
Figure 3:
Figure 3:. Schematic of a muscle cell and the proteins linked to the nuclear envelope.
A) Nuclear import and export through nuclear pore complexes requires transport receptors such as importins, exportins and transportins. These proteins shuttle cargo through the NPC along using a GTP gradient generated by RAN GTPase. B) The LINC complex connects lamins that compose the nuclear matrix on the inside of the nuclear envelope with via a family of proteins termed SUN1/2 and the outer nuclear envelope via a family proteins with a KASH domain (Nesprins) that then connect to the actin, intermediate filament and microtubule network.
Figure 4 |
Figure 4 |. The triad is a muscle-specific substructure that is critical for mediating excitation contraction coupling
The triad represents the apposition of a Transverse (T)-tubule with two terminal cisternae of the sarcoplasmic reticulum (SR). While many types of proteins and regulatory structures located in or around the triad have been identified, the mechanisms of T-tubule biogenesis and triad formation are still incompletely understood. a | A muscle fiber is excited by the motor neuron at the neuromuscular junction, inducing membrane depolarization, which travels along the sarcolemma and into the t-tubule. The dihydropyridine receptor (DHPR) senses membrane depolarization, and undergoes a conformation change which activates the ryanodine receptor (RYR1), releasing Ca2+ from the SR into the sarcoplasm. Sarcoplasmic Ca2+ then binds to the troponin complex, releasing inhibition and initiating a muscle contraction. Several other proteins are critical for the formation and maintenance of the triad. MTM1 potentially regulates transport of muscle-specific proteins to the triad. BIN1 is involved in membrane remodelling, and in concert with caveole, initiates T tubule formation. DNM2 is speculated to function in parallel (and potentially opposed) to BIN1, via its membrane fission activity, to modulate T-tubule formation and maintenance. Two examples of mutations and their consequences on the triad: b | DNM2 hyperactivity leads to aberrant/premature membrane fission and abnormal t-tubule formation; b’ | RYR1 mutations lead to impaired calcium release and reduced muscle contraction.
Figure 5 |
Figure 5 |. Skeletal Muscle Membrane Repair.
Skeletal muscle sustains small tears from normal muscle use, which are quickly repaired by cell repair machinery. a | Following a tear, calcium flows down its concentration gradient from outside the cell to inside. Cholesterol is oxidized and phosphatidyl serine changes its conformation from intracellular-facing to extracellular facing. b | Calcium, oxidized cholesterol and phospholipids activate the cellular repair machinery. Annexin proteins bind to calcium and phosphatidyl serine and form a cap that seals the are of the tear.
Figure 6 |
Figure 6 |. Schematic of a muscle cell and the proteins linked to protein turnover and quality control.
b | Skeletal muscle mass is maintained by the balance of protein synthesis and protein degradation. b | Disruptions in chaperone surveillance, the ubiquitin proteasome system and the autophago-lysosomal pathway lead to pathologic changes in skeletal muscle that include myofibrillar disruption, inclusion bodies, protein aggregates and vacuolation.
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