Skeletal Muscle Involvement in Patients With Truncations of Titin and Familial Dilated Cardiomyopathy,JACC: Heart Failure

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Skeletal Muscle Involvement in Patients With Truncations of Titin and Familial Dilated Cardiomyopathy
JACC: Heart Failure ( IF 10.3 ) Pub Date : 2023-11-22 , DOI: 10.1016/j.jchf.2023.10.010
Sofie Vinther Skriver ₁ , Bjørg Krett ₁ , Nanna Scharf Poulsen ₁ , Thomas Krag ₁ , Helle Rudkjær Walas ₁ , Alex Hørby Christensen ₂ , Henning Bundgaard ₃ , John Vissing ₄ , Christoffer Rasmus Vissing ₅

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Genetic variants in titin () are associated with dilated cardiomyopathy (DCM) and skeletal myopathy. However, the skeletal muscle phenotype in individuals carrying heterozygous truncating variants (TTNtv), the leading cause of DCM, is understudied. This study aimed to assess the skeletal muscle phenotype associated with TTNtv. Participants with TTNtv were included in a cross-sectional study. Skeletal muscle fat fraction was evaluated by magnetic resonance imaging (compared with healthy controls and controls with non-TTNtv DCM). Muscle strength was evaluated by dynamometry and muscle biopsy specimens were analyzed. Twenty-five TTNtv participants (11 women, mean age 51 ± 15 years, left ventricular ejection fraction 45% ± 10%) were included (19 had DCM). Compared to healthy controls (n = 25), fat fraction was higher in calf (12.5% vs 9.9%, = 0.013), thigh (12.2% vs 9.3%, = 0.004), and paraspinal muscles (18.8% vs 13.9%, = 0.008) of TTNtv participants. Linear mixed effects modelling found higher fat fractions in TTNtv participants compared to healthy controls (2.5%; 95% CI: 1.4-3.7; < 0.001) and controls with non-TTNtv genetic DCM (n = 7) (1.5%; 95% CI: 0.2-2.8; = 0.025). Muscle strength was within 1 SD of normal values. Biopsy specimens from 21 participants found myopathic features in 13 (62%), including central nuclei. Electron microscopy showed well-ordered Z-lines and T-tubuli but uneven and discontinuous M-lines and excessive glycogen depositions flanked by autophagosomes, lysosomes, and abnormal mitochondria with mitophagy. Mild skeletal muscle involvement was prevalent in patients with TTNtv. The phenotype was characterized by an increased muscle fat fraction and excessive accumulation of glycogen, possibly due to reduced autophagic flux. These findings indicate an impact of TTNtv beyond the heart.

中文翻译：

肌联蛋白截短和家族性扩张型心肌病患者的骨骼肌受累

titin () 的遗传变异与扩张型心肌病 (DCM) 和骨骼肌病有关。然而，携带杂合截断变异 (TTNtv) 的个体的骨骼肌表型（DCM 的主要原因）尚未得到充分研究。本研究旨在评估与 TTNtv 相关的骨骼肌表型。 TTNtv 的参与者被纳入一项横断面研究。通过磁共振成像评估骨骼肌脂肪分数（与健康对照和非 TTNtv DCM 对照相比）。通过测力法评估肌肉力量并分析肌肉活检标本。 25 名 TTNtv 参与者（11 名女性，平均年龄 51 ± 15 岁，左心室射血分数 45% ± 10%）被纳入其中（19 名患有扩张型心肌病）。与健康对照组 (n = 25) 相比，小腿 (12.5% vs 9.9%, = 0.013)、大腿 (12.2% vs 9.3%, = 0.004) 和椎旁肌肉 (18.8% vs 13.9%, =) 的脂肪分数较高0.008) 的 TTNtv 参与者。线性混合效应模型发现，与健康对照（2.5%；95% CI：1.4-3.7；< 0.001）和非 TTNtv 遗传性 DCM 对照（n = 7）相比，TTNtv 参与者的脂肪分数更高（1.5%；95% CI）：0.2-2.8；=0.025）。肌肉力量在正常值的 1 SD 范围内。 21 名参与者的活检标本发现 13 名参与者（62%）有肌病特征，包括中央核。电子显微镜显示有序的 Z 线和 T 管，但不均匀和不连续的 M 线，以及两侧有自噬体、溶酶体和线粒体自噬异常线粒体的过量糖原沉积。 TTNtv 患者普遍存在轻度骨骼肌受累。该表型的特征是肌肉脂肪分数增加和糖原过度积累，这可能是由于自噬通量减少所致。这些发现表明 TTNtv 的影响超出了心脏范围。

更新日期：2023-11-22

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