Titin‐based mechanosensing modulates muscle hypertrophy

Pijl, Robbert van der; Strom, Joshua; Conijn, Stefan; Lindqvist, Johan; Labeit, Siegfried; Granzier, Henk; Ottenheijm, Coen A.C.

doi:10.1002/jcsm.12319

Cited by 45 publications

(46 citation statements)

References 56 publications

(94 reference statements)

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“…Hundred-day-old male C57BL/6J mice (n = 9 UDD and n = 7 sham) and 58-to 70-day-old cLmod2 KO mice (n = 10 KO UDD and n = 4 WT UDD) were anaesthetized with 1 to 3% isoflurane, and a small incision was made in the neck area just above the clavicle. The phrenic nerve on the right side was isolated behind the sternohyoid muscle, and a 3-to 4-mm section was transected at the height of the supraclavicular nerve branch (23). Mice were closed up, allowed to recover, and were sacrificed 30 hours after denervation for tissue harvest.…”

Section: Udd Surgerymentioning

confidence: 99%

Nebulin and Lmod2 are critical for specifying thin-filament length in skeletal muscle

et al. 2020

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Regulating the thin-filament length in muscle is crucial for controlling the number of myosin motors that generate power. The giant protein nebulin forms a long slender filament that associates along the length of the thin filament in skeletal muscle with functions that remain largely obscure. Here nebulin’s role in thin-filament length regulation was investigated by targeting entire super-repeats in the Neb gene; nebulin was either shortened or lengthened by 115 nm. Its effect on thin-filament length was studied using high-resolution structural and functional techniques. Results revealed that thin-filament length is strictly regulated by the length of nebulin in fast muscles. Nebulin’s control is less tight in slow muscle types where a distal nebulin-free thin-filament segment exists, the length of which was found to be regulated by leiomodin-2 (Lmod2). We propose that strict length control by nebulin promotes high-speed shortening and that dual-regulation by nebulin/Lmod2 enhances contraction efficiency.

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Section: Udd Surgerymentioning

confidence: 99%

Nebulin and Lmod2 are critical for specifying thin-filament length in skeletal muscle

et al. 2020

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“…Appropriate respiratory management usually results in a normal lifespan [73]. To date, over 200 NM-causing pathogenic variants have been identified throughout the entire length of NEB [32,44,64,65]. Variants in NEB can also cause disorders described as distal nebulin myopathy [84], distal NM [45], foetal akinesia/lethal multiple pterygium syndrome [1,44] and, in rare cases, core-rod myopathy [71].…”

Section: Introductionmentioning

confidence: 99%

Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb

Laitila

McNamara

Wingate

et al. 2020

acta neuropathol commun

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Nemaline myopathy (NM) caused by mutations in the gene encoding nebulin (NEB) accounts for at least 50% of all NM cases worldwide, representing a significant disease burden. Most NEB-NM patients have autosomal recessive disease due to a compound heterozygous genotype. Of the few murine models developed for NEB-NM, most are Neb knockout models rather than harbouring Neb mutations. Additionally, some models have a very severe phenotype that limits their application for evaluating disease progression and potential therapies. No existing murine models possess compound heterozygous Neb mutations that reflect the genotype and resulting phenotype present in most patients. We aimed to develop a murine model that more closely matched the underlying genetics of NEB-NM, which could assist elucidation of the pathogenetic mechanisms underlying the disease. Here, we have characterised a mouse strain with compound heterozygous Neb mutations; one missense (p.Tyr2303His), affecting a conserved actin-binding site and one nonsense mutation (p.Tyr935*), introducing a premature stop codon early in the protein. Our studies reveal that this compound heterozygous model, Neb Y2303H, Y935X , has striking skeletal muscle pathology including nemaline bodies. In vitro whole muscle and single myofibre physiology studies also demonstrate functional perturbations. However, no reduction in lifespan was noted. Therefore, Neb Y2303H,Y935X mice recapitulate human NEB-NM and are a much needed addition to the NEB-NM mouse model collection. The moderate phenotype also makes this an appropriate model for studying NEB-NM pathogenesis, and could potentially be suitable for testing therapeutic applications.

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“…D: the cumulative hypertrophy (longitudinal combined with cross-sectional hypertrophy, displayed as a percent increase in costal diaphragm fiber volume, compared with sham operated animals) was reduced in the mice with compliant titin and increased in the mice with stiff titin. response (76). The nature of this regulatory role remains to be established, but we postulate that changes in the strain imposed on titin affects the binding of MARP1 and forms a signaling complex that regulates muscle trophicity.…”

Section: Titin: a Giant Mechanosensor Proteinmentioning

confidence: 94%

“…Other titin-binding proteins include the transcription regulator four and a half LIM domains protein 1 (FHL1), which locates to titin's elastic I-band region. FHL1 has been linked to both skeletal muscle hypertrophy and dystrophy, and our group has shown that passive muscle stretch enhances its expression (76). A possible pathway by which this happens is that increased load on titin changes the binding affinity of FHL1 for titin, which shifts the distribution between the titin-bound and nuclear-bound pools of FHL1 thus altering gene expression (including that of FHL1 itself).…”

Section: Titin: a Giant Mechanosensor Proteinmentioning

confidence: 99%

Diaphragm contractile weakness due to reduced mechanical loading: role of titin

Pijl

Granzier

Ottenheijm

2019

American Journal of Physiology-Cell Physiology

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The diaphragm, the main muscle of inspiration, is constantly subjected to mechanical loading. Only during controlled mechanical ventilation, as occurs during thoracic surgery and in the intensive care unit, is mechanical loading of the diaphragm arrested. Animal studies indicate that the diaphragm is highly sensitive to unloading, causing rapid muscle fiber atrophy and contractile weakness; unloading-induced diaphragm atrophy and contractile weakness have been suggested to contribute to the difficulties in weaning patients from ventilator support. The molecular triggers that initiate the rapid unloading atrophy of the diaphragm are not well understood, although proteolytic pathways and oxidative signaling have been shown to be involved. Mechanical stress is known to play an important role in the maintenance of muscle mass. Within the muscle's sarcomere, titin is considered to play an important role in the stress-response machinery. Titin is a giant protein that acts as a mechanosensor regulating muscle protein expression in a sarcomere strain-dependent fashion. Thus titin is an attractive candidate for sensing the sudden mechanical arrest of the diaphragm when patients are mechanically ventilated, leading to changes in muscle protein expression. Here, we provide a novel perspective on how titin and its biomechanical sensing and signaling might be involved in the development of mechanical unloading-induced diaphragm weakness.

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Titin‐based mechanosensing modulates muscle hypertrophy

Cited by 45 publications

References 56 publications

Nebulin and Lmod2 are critical for specifying thin-filament length in skeletal muscle

Nebulin and Lmod2 are critical for specifying thin-filament length in skeletal muscle

Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb

Diaphragm contractile weakness due to reduced mechanical loading: role of titin

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