Titin-based stiffening of muscle fibers in Ehlers-Danlos Syndrome

Ottenheijm, Coen A.C.; Voermans, Nicol C.; Hudson, Bryan D.; Irving, Thomas C.; Stienen, G. J. M.; Engelen, B.G.M. van; Granzier, Henk

doi:10.1152/japplphysiol.01166.2011

Cited by 36 publications

(33 citation statements)

References 41 publications

(63 reference statements)

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“…Horowits and Podolsky (1987) and Horowits and colleagues (1989) also showed that without force transmission by titin, force generation by the cross-bridges is highly inefficient because energy from crossbridge interactions is lost to thick filament displacement at the expense of longitudinal tension. Numerous other studies also show that changes in titin isoforms and consequent changes in titin-based stiffness are associated with changes in force production (Ottenheijm et al, 2012;Pulcastro et al, 2016). We suggest that the force deficit in mdm muscles is due to impaired transmission of force from the cross-bridges to the Z-lines.…”

Section: Titin Activation and The Mdm Mutationsupporting

confidence: 58%

Effects of activation on the elastic properties of intact soleus muscles with a deletion in titin

Monroy

Powers

Pace

et al. 2016

Journal of Experimental Biology

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Titin has long been known to contribute to muscle passive tension. Recently, it was also demonstrated that titin-based stiffness increases upon Ca 2+ activation of wild-type mouse psoas myofibrils stretched beyond overlap of the thick and thin filaments. In addition, this increase in titin-based stiffness was impaired in single psoas myofibrils from mdm mice, characterized by a deletion in the N2A region of the Ttn gene. Here, we investigated the effects of activation on elastic properties of intact soleus muscles from wild-type and mdm mice to determine whether titin contributes to active muscle stiffness. Using load-clamp experiments, we compared the stress-strain relationships of elastic elements in active and passive muscles during unloading, and quantified the change in stiffness upon activation. Results from wild-type muscles show that upon activation, the elastic modulus increases, elastic elements develop force at 15% shorter lengths, and there was a 2.9-fold increase in the slope of the stress-strain relationship. These results are qualitatively and quantitatively similar to results from single wild-type psoas myofibrils. In contrast, mdm soleus showed no effect of activation on the slope or intercept of the stress-strain relationship, which is consistent with impaired titin activation observed in single mdm psoas myofibrils. Therefore, it is likely that titin plays a role in the increase of active muscle stiffness during rapid unloading. These results are consistent with the idea that, in addition to the thin filaments, titin is activated upon Ca 2+ influx in skeletal muscle.

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Section: Titin Activation and The Mdm Mutationsupporting

confidence: 58%

Effects of activation on the elastic properties of intact soleus muscles with a deletion in titin

Monroy

Powers

Pace

et al. 2016

Journal of Experimental Biology

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“…Single muscle fibers were isolated from the muscle biopsies and demembranated for 20 minutes in a relaxing solution containing 1% Triton X-100 at ;4°C. 4,5 Triton permeabilizes all membranous structures, allowing for activation of the sarcomere with exogenous Ca 21 and enabling study of sarcomeric function in isolation. On average, 9 fibers were prepared per biopsy.…”

Section: Discussionmentioning

confidence: 99%

“…Experimental details have been described previously. 4,5 In brief, isolated single muscle fibers were mounted between a force transducer and a length motor. Maximum force-generating capacity was measured at a sarcomere length of 2.5 mm by activating the fibers in a saturating [Ca 21 ] solution.…”

Section: Discussionmentioning

confidence: 99%

“…Maximum force-generating capacity was measured at a sarcomere length of 2.5 mm by activating the fibers in a saturating [Ca 21 ] solution. 4,5 Force was normalized to muscle fiber cross-sectional area. Various submaximal Ca 21 concentrations were used to assess the Ca 21 sensitivity of force generation.…”

Section: Discussionmentioning

confidence: 99%

“…Various submaximal Ca 21 concentrations were used to assess the Ca 21 sensitivity of force generation. 4,5 We measured passive force at a sarcomere length of 2.5 mm by imposing length changes on relaxed muscle fibers. 5 Myosin heavy chain isoform composition was determined by sodium dodecyl sulfate polyacrylamide gel electrophoresis.…”

Section: Discussionmentioning

confidence: 99%

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Sarcomeric dysfunction contributes to muscle weakness in facioscapulohumeral muscular dystrophy

et al. 2013

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Objective: To investigate whether sarcomeric dysfunction contributes to muscle weakness in facioscapulohumeral muscular dystrophy (FSHD).Methods: Sarcomeric function was evaluated by contractile studies on demembranated single muscle fibers obtained from quadriceps muscle biopsies of 4 patients with FSHD and 4 healthy controls. The sarcomere length dependency of force was determined together with measurements of thin filament length using immunofluorescence confocal scanning laser microscopy. X-ray diffraction techniques were used to study myofilament lattice spacing.Results: FSHD muscle fibers produced only 70% of active force compared to healthy controls, a reduction which was exclusive to type II muscle fibers. Changes in force were not due to changes in thin filament length or sarcomere length. Passive force was increased 5-to 12-fold in both fiber types, with increased calcium sensitivity of force generation and decreased myofilament lattice spacing, indicating compensation by the sarcomeric protein titin. Conclusions:We have demonstrated a reduction in sarcomeric force in type II FSHD muscle fibers, and suggest compensatory mechanisms through titin stiffening. Based on these findings, we propose that sarcomeric dysfunction plays a critical role in the development of muscle weakness in FSHD. Although muscle weakness is the hallmark feature of facioscapulohumeral muscular dystrophy (FSHD), the molecular mechanisms underlying weakness remain largely unknown. Before treatment options can be pursued, more insight into the pathophysiologic mechanisms of muscle weakness in FSHD is needed.To understand why FSHD muscles are weak, we can take a clue from the genetics of the disease. FSHD1, the most common type of FSHD, is caused by a contraction of D4Z4, a 3.3-kb macrosatellite repeat located on chromosome 4q35. This contraction changes chromatin configuration, which is hypothesized to permit transcription of otherwise epigenetically silenced genes. 1Of the candidate genes currently under investigation, some are muscle-specific and encode proteins involved in musculogenesis and the development of the sarcomere-the smallest contractile unit in muscle. Gene expression profiling studies in FSHD muscle biopsies have shown dysregulation of several sarcomeric proteins.2 Overexpression of DUX4, the leading FSHD candidate gene, has been shown to activate pathways involved in sarcomeric protein degradation. Despite evidence pointing toward changes on the level of the sarcomere, no studies have examined whether sarcomeric dysfunction contributes to muscle weakness in FSHD. This study is the first to report on sarcomeric function in FSHD.

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The neuromuscular differential diagnosis of joint hypermobility

Donkervoort¹,

Bönnemann²,

Loeys³

et al. 2015

American J of Med Genetics Pt C

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Joint hypermobility is the defining feature of various inherited connective tissue disorders such as Marfan syndrome and various types of Ehlers-Danlos syndrome and these will generally be the first conditions to be considered by geneticists and pediatricians in the differential diagnosis of a patient presenting with such findings. However, several congenital and adult-onset inherited myopathies also present with joint hypermobility in the context of often only mild-to-moderate muscle weakness and should, therefore, be included in the differential diagnosis of joint hypermobility. In fact, on the molecular level disorders within both groups represent different ends of the same spectrum of inherited extracellular matrix (ECM) disorders. In this review we will summarize the measures of joint hypermobility, illustrate molecular mechanisms these groups of disorders have in common, and subsequently discuss the clinical features of: 1) the most common connective tissue disorders with myopathic or other neuromuscular features: Ehlers-Danlos syndrome, Marfan syndrome and Loeys-Dietz syndrome; 2) myopathy and connective tissue overlap disorders (muscle extracellular matrix (ECM) disorders), including collagen VI related dystrophies and FKBP14 related kyphoscoliotic type of Ehlers-Danlos syndrome; and 3) various (congenital) myopathies with prominent joint hypermobility including RYR1- and SEPN1-related myopathy. The aim of this review is to assist clinical geneticists and other clinicians with recognition of these disorders.

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Titin-based stiffening of muscle fibers in Ehlers-Danlos Syndrome

Cited by 36 publications

References 41 publications

Effects of activation on the elastic properties of intact soleus muscles with a deletion in titin

Effects of activation on the elastic properties of intact soleus muscles with a deletion in titin

Sarcomeric dysfunction contributes to muscle weakness in facioscapulohumeral muscular dystrophy

The neuromuscular differential diagnosis of joint hypermobility

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