睾丸切除术和肢体固定相结合再现了小鼠骨骼肌早期与年龄有关的变化

JCSM rapid communications Pub Date : 2024-04-16 DOI:10.1002/rco2.90

Danielle A. Debruin, Jasmaine Murphy, Dean G. Campelj, Ryan Bagaric, Cara A. Timpani, Craig A. Goodman, Erik D. Hanson, Emma Rybalka, Alan Hayes

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引用次数: 0

摘要

背景肌肉质量和功能在中年时会下降，最终导致老年人肌肉疏松症和不良的健康状况，降低生活质量。目前缺乏成本低、时间短、效果好的小鼠模型来再现肌肉质量下降的相关生理变化，从而研究延缓肌肉疏松症的可能干预措施。我们旨在评估睾丸切除手术（ORC）模拟与年龄相关的雄激素下降和后肢固定（IM）在诱导与年龄相关的骨骼肌变化方面的有效性。方法对四个月大的雄性 C57BL/6J 小鼠（n = 10）进行睾丸切除手术，然后进行为期 14 天的右后肢固定。铸造期结束后，评估体内外肌肉收缩功能、组织学和各种线粒体标记物，并将结果与年龄匹配的对照组（CON；n = 8）和中年组（MA；12 ± 1 个月，n = 9）动物进行比较。结果 IM 与 ORC 联用会导致后肢多块肌肉的肌肉质量下降 30%-40%（P < 0.0001），根据体重校正后，肌肉损失的程度与 MA 组相当（P < 0.0001）。与对侧肢体（P <0.05）和年龄匹配的CON组（P <0.05）相比，ORC小鼠IM肢体的比目鱼肌力显著下降。与对照组相比，ORC 小鼠肢体肌力和肌肉质量下降的同时，肌肉结构蛋白肌营养不良蛋白和各种线粒体标记物的表达也减少了 70%，其中包括细胞色素 C（-55%）、过氧化物酶体增殖激活受体伽马共激活因子 1-β（PGC1-β）（-49%）和细胞色素氧化酶 IV（COX-IV）（-73%）（P < 0.001）。最后，我们的模型还显示了快慢肌特定纤维类型的变化，这与 MA 组的变化相似。结论在 IM 期间应用治疗方法可针对 MA 成年人的急性肌肉萎缩，而在低睾酮环境中拆除石膏后应用治疗方法可代表康复疗法的一个窗口。

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Combined orchiectomy and limb immobilization recapitulate early age-related changes to skeletal muscle in mice

Background

Muscle mass and function decline in middle age, ultimately resulting in sarcopenia in the elderly and poor health outcomes, reducing quality of life. There is a lack of cost- and time-effective murine models that recapitulate the physiological changes associated with muscle mass decline to study possible interventions to delay sarcopenia. We aimed to evaluate the effectiveness of combining orchiectomy (ORC) surgery to simulate age-related androgen decline and hindlimb immobilization (IM) in inducing age-related skeletal muscle changes.

Methods

Four-month-old male C57BL/6J mice (n = 10) were subjected to ORC, followed by IM (right hindlimb casting) for 14 days. Upon completion of the casting period, ex vivo muscle contractile function, histology, and various mitochondrial markers were assessed, and results were compared with age-matched controls (CON; n = 8) and middle-aged (MA; 12 ± 1 months, n = 9) animals.

Results

IM combined with ORC induced a 30%–40% decrease in muscle mass across multiple hindlimb muscles (P < 0.0001), with the magnitude of muscle loss comparable with the MA group when corrected for body weight (P < 0.0001). In the IM limb of ORC mice, soleus muscle force significantly decreased when compared with the contralateral limb (P < 0.05) and aged-matched CON group (P < 0.05). The decrements in muscle force and mass present in the IM limb of ORC mice were accompanied by a 70% reduction in the expression of the muscle structural protein dystrophin and various mitochondrial markers, including cytochrome C (−55%), peroxisome proliferator-activated receptor gamma co-activator 1-beta (PGC1-β) (−49%), and cytochrome oxidase IV (COX-IV) (−73%) when compared with CON animals (P < 0.001). Lastly, our model also demonstrated specific fibre-type shifts in fast- and slow-twitch muscles, which mimicked changes in the MA group.

Conclusions

Applying treatments during IM could target acute muscle atrophy in MA adults, while applying them following cast removal in a low-testosterone environment could represent a window for rehabilitation therapeutics.

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