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- Fig. 1.
Contraction and relaxation in skeletal muscle. (1) In healthy skeletal muscle, an action potential from the motor neuron triggers acetylcholine (ACh) release at the neuromuscular junction, which induces an action potential along the muscle myofiber sarcolemma. The signal is propagated along the sarcolemma and the network of deep invaginations called T-tubules. T-tubules (shown here in dashed box) together with two terminal cisternae of the sarcoplasmic reticulum (SR), the main Ca2+-storage region in skeletal muscle, form the triad. The triad is central to excitation-contraction coupling (ECC), the process by which an action potential triggers the synchronous contraction of the myofibrils, leading to muscle contraction. (2) The change in membrane potential at the T-tubule caused by the action potential triggers a conformational change to the voltage-sensor subunit of the dihydropyridine receptor (DHPR), which triggers the opening of RYR1 in the terminal cisternae of the SR, to which it is mechanically coupled. RYR1 releases large amounts of Ca2+ into the sarcoplasm, where it interacts with the repeating contractile units of the myofibrils, called sarcomeres. (3) Ca2+ binds to the troponin complex, triggering the reconfiguration of the actin-tropomyosin structure, which exposes myosin-binding sites and allows myosin heads to bind to actin via crosslinks. Cyclical actin-myosin binding shortens the sarcomere via the sliding-filament mechanism first theorized by Huxley, Hansom and Niedergerke in 1954 (Huxley and Hanson, 1954; Huxley and Niedergerke, 1954). This results in muscle contraction. (4) Repolarization of the sarcolemma and T-tubules closes the DHPR and RYR1, preventing further Ca2+ release. Sarcoplasmic Ca2+ is rapidly sequestered into the SR via sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) pumps, which enable the actin-tropomyosin structure to return to its original conformation, blocking myosin-head binding and resulting in muscle relaxation (5) (Gomes et al., 2002; Smith et al., 2016). See Box 3 for a glossary of certain terms.
- Fig. 2.
Skeletal-muscle tissue sections from patients with core myopathy. (A-D) Central core disease; (E,F) MmD. Samples range in age: 12 years (A,B), 28 years (C,D), 34 years (E,F). (A) Muscle shows myopathic features with fiber size variation and a mild increase in perimysial connective tissue with focal fatty infiltration and (B) a single central or eccentric core in most type 1 fibers. (C) Mild fiber size variation is shown. (D) Central cores are only present in the minority of type 1 fibers. (E) Myopathic features with fiber size variability and multiple central nuclei. (F) Multi-minicores in type 1 and type 2 fibers (Box 3) are shown. All patients carry RYR1 mutations. *, fiber size variation; +, increase in perimysial connective tissue: ^, points to central core; §, eccentric core: °, multi-minicores. Image credit: E.P.
- Fig. 3.
The proteins currently identified as causing core myopathies, and their location in skeletal muscle. Disease-associated proteins are identified in the Key. Schematic of a multinucleate myofiber with associated satellite cell, with a magnified region of the myofiber showing the excitation-contraction coupling (ECC) apparatus, sarcoplasmic reticulum (SR), sarcomere and mitochondria. CASQ1, calsequestrin 1; CCD78, coiled-coil domain-containing protein 78; DHPR, dihydropyridine receptor; FXR1, fragile X related 1; MEGF10, multiple epidermal growth factor-like domains protein 10; MYH7, myosin heavy chain gene; RYR1, ryanodine receptor 1; SELENON, selenoprotein N; SERCA, sarco/endoplasmic reticulum Ca2+-ATPase.
- Fig. 4.
The different methods in which to quantify the pathology of core myopathies. COX, cytochrome oxidase; ECC, excitation-contraction coupling; FRET, fluorescence resonance energy transfer; NADH, nicotinamide adenine dinucleotide; SDH, succinate dehydrogenase; TBARS, thiobarbituric acid-reactive substances; TMRE, tetramethylrhodamine ethyl ester.
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