Pilot investigations into the mechanistic basis for adverse effects of glucocorticoids in dysferlinopathy.

IF 5.3 2区医学 Q2 CELL BIOLOGY

Skeletal Muscle Pub Date : 2024-08-09 DOI:10.1186/s13395-024-00350-6

Erin M Lloyd, Rachael C Crew, Vanessa R Haynes, Robert B White, Peter J Mark, Connie Jackaman, John M Papadimitriou, Gavin J Pinniger, Robyn M Murphy, Matthew J Watt, Miranda D Grounds

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引用次数: 0

Abstract

Background: Dysferlinopathies are a clinically heterogeneous group of muscular dystrophies caused by gene mutations resulting in deficiency of the membrane-associated protein dysferlin. They manifest post-growth and are characterised by muscle wasting (primarily in the limb and limb-gridle muscles), inflammation, and replacement of myofibres with adipose tissue. The precise pathomechanism for dysferlinopathy is currently unclear; as such there are no treatments currently available. Glucocorticoids (GCs) are widely used to reduce inflammation and treat muscular dystrophies, but when administered to patients with dysferlinopathy, they have unexpected adverse effects, with accelerated loss of muscle strength.

Methods: To investigate the mechanistic basis for the adverse effects of GCs in dysferlinopathy, the potent GC dexamethasone (Dex) was administered for 4-5 weeks (0.5-0.75 µg/mL in drinking water) to dysferlin-deficient BLA/J and normal wild-type (WT) male mice, sampled at 5 (Study 1) or 10 months (Study 2) of age. A wide range of analyses were conducted. Metabolism- and immune-related gene expression was assessed in psoas muscles at both ages and in quadriceps at 10 months of age. For the 10-month-old mice, quadriceps and psoas muscle histology was assessed. Additionally, we investigated the impact of Dex on the predominantly slow and fast-twitch soleus and extensor digitorum longus (EDL) muscles (respectively) in terms of contractile function, myofibre-type composition, and levels of proteins related to contractile function and metabolism, plus glycogen.

Results: At both ages, many complement-related genes were highly expressed in BLA/J muscles, and WT mice were generally more responsive to Dex than BLA/J. The effects of Dex on BLA/J mice included (i) increased expression of inflammasome-related genes in muscles (at 5 months) and (ii) exacerbated histopathology of quadriceps and psoas muscles at 10 months. A novel observation was pronounced staining for glycogen in many myofibres of the damaged quadriceps muscles, with large pale vacuolated myofibres, suggesting possible myofibre death by oncosis.

Conclusion: These pilot studies provide a new focus for further investigation into the adverse effects of GCs on dysferlinopathic muscles.

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对糖皮质激素在铁蛋白异常病中产生不良影响的机理基础的试验性研究。

背景：脱钙铁蛋白病是一组临床上异质性的肌肉萎缩症，由基因突变导致膜相关蛋白脱钙铁蛋白缺乏引起。它们表现为生长后肌肉萎缩（主要是四肢和肢栅肌肉）、炎症和脂肪组织替代肌纤维。铁蛋白吸收障碍症的确切病理机制目前尚不清楚，因此目前还没有治疗方法。糖皮质激素（GCs）被广泛用于减轻炎症和治疗肌肉萎缩症，但当给铁蛋白沉积症患者用药时，它们会产生意想不到的不良反应，加速肌肉力量的丧失：为了研究GCs在铁蛋白障碍病中产生不良影响的机理基础，给铁蛋白障碍的BLA/J雄性小鼠和正常野生型（WT）雄性小鼠注射强效GC地塞米松（Dex）4-5周（在饮用水中添加0.5-0.75 µg/mL），在小鼠5个月大（研究1）或10个月大（研究2）时取样。研究进行了一系列分析。对两个月龄的腰肌和 10 个月龄的股四头肌进行了代谢和免疫相关基因表达评估。对 10 个月大的小鼠股四头肌和腰肌组织学进行了评估。此外，我们还从收缩功能、肌纤维类型组成、与收缩功能和新陈代谢有关的蛋白质水平以及糖原等方面研究了 Dex 对主要为慢肌腱和快肌腱的比目鱼肌和伸拇肌（EDL）的影响：在两个年龄段，许多补体相关基因在 BLA/J 肌肉中都有高表达，WT 小鼠对 Dex 的反应通常比 BLA/J 小鼠更敏感。Dex 对 BLA/J 小鼠的影响包括：(i) 肌肉中炎性体质相关基因的表达增加（5 个月时）；(ii) 股四头肌和腰肌的组织病理学恶化（10 个月时）。一个新的观察结果是，受损股四头肌的许多肌纤维都出现了明显的糖原染色，并伴有大片苍白的空泡化肌纤维，这表明肌纤维可能因肿瘤死亡：这些试点研究为进一步研究 GCs 对铁蛋白病肌肉的不良影响提供了新的焦点。

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来源期刊

Skeletal Muscle CELL BIOLOGY-

CiteScore

9.10

自引率

0.00%

发文量

审稿时长

12 weeks

期刊介绍： The only open access journal in its field, Skeletal Muscle publishes novel, cutting-edge research and technological advancements that investigate the molecular mechanisms underlying the biology of skeletal muscle. Reflecting the breadth of research in this area, the journal welcomes manuscripts about the development, metabolism, the regulation of mass and function, aging, degeneration, dystrophy and regeneration of skeletal muscle, with an emphasis on understanding adult skeletal muscle, its maintenance, and its interactions with non-muscle cell types and regulatory modulators. Main areas of interest include: -differentiation of skeletal muscle- atrophy and hypertrophy of skeletal muscle- aging of skeletal muscle- regeneration and degeneration of skeletal muscle- biology of satellite and satellite-like cells- dystrophic degeneration of skeletal muscle- energy and glucose homeostasis in skeletal muscle- non-dystrophic genetic diseases of skeletal muscle, such as Spinal Muscular Atrophy and myopathies- maintenance of neuromuscular junctions- roles of ryanodine receptors and calcium signaling in skeletal muscle- roles of nuclear receptors in skeletal muscle- roles of GPCRs and GPCR signaling in skeletal muscle- other relevant aspects of skeletal muscle biology. In addition, articles on translational clinical studies that address molecular and cellular mechanisms of skeletal muscle will be published. Case reports are also encouraged for submission. Skeletal Muscle reflects the breadth of research on skeletal muscle and bridges gaps between diverse areas of science for example cardiac cell biology and neurobiology, which share common features with respect to cell differentiation, excitatory membranes, cell-cell communication, and maintenance. Suitable articles are model and mechanism-driven, and apply statistical principles where appropriate; purely descriptive studies are of lesser interest.