高寒环境通过诱导骨骼肌萎缩与纤维化协同加重骨关节炎病理进程

藤培煜; 李松; 龙尘宇; 黄俊兰; 杨鹏; 苏楠; 罗小庆; 杨京; 张若彬; 谢杨丽; 陈林

doi:10.16016/j.2097-0927.202511078

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高寒环境通过诱导骨骼肌萎缩与纤维化协同加重骨关节炎病理进程

基础医学 | 更新时间：2026-01-14

- 高寒环境通过诱导骨骼肌萎缩与纤维化协同加重骨关节炎病理进程
- Cold exposure exacerbates osteoarthritis via synergistic muscle atrophy and fibrosis
- 陆军军医大学学报 2026年48卷第1期页码：42-53
- 作者机构：
  
  陆军军医大学大坪医院战伤组织修复与康复医学研究室，重庆
- 作者简介：
  
  谢杨丽，E-mail：xieyangli841015@163.com
  陈林，E-mail：linchen70@163.com
- 基金信息：
  
  国家自然科学基金重大项目(82394444);重庆市科卫联合项目(2024DBXM008);后勤科研重点项目(BLJ22J014)
- DOI：10.16016/j.2097-0927.202511078
  中图分类号： R322.74;R339.55;R684.3
- 收稿：2025-10-25，
  
  修回：2025-11-21，
  
  录用：2025-12-15，
  
  纸质出版：2026-01-15
- 稿件说明：
移动端阅览
藤培煜，李松，龙尘宇，等.高寒环境通过诱导骨骼肌萎缩与纤维化协同加重骨关节炎病理进程［J］.陆军军医大学学报，2026，48（01）：42-53.DOI：10.16016/j.2097-0927.202511078.

TENG P Y，LI S，LONG C Y，et al.Cold exposure exacerbates osteoarthritis via synergistic muscle atrophy and fibrosis［J］.J Army Med Univ，2026，48（01）：42-53.DOI：10.16016/j.2097-0927.202511078.
藤培煜，李松，龙尘宇，等.高寒环境通过诱导骨骼肌萎缩与纤维化协同加重骨关节炎病理进程［J］.陆军军医大学学报，2026，48（01）：42-53.DOI：10.16016/j.2097-0927.202511078. DOI：

TENG P Y，LI S，LONG C Y，et al.Cold exposure exacerbates osteoarthritis via synergistic muscle atrophy and fibrosis［J］.J Army Med Univ，2026，48（01）：42-53.DOI：10.16016/j.2097-0927.202511078. DOI：

摘要

目的

探讨高寒环境对骨骼肌功能及骨关节炎病理进程的影响，旨在揭示寒冷条件下骨骼肌萎缩、纤维化与关节退变之间的相互作用机制，为高寒地区官兵运动系统健康防护提供理论依据。

方法

40只11周龄C57BL/6雄性小鼠按内侧半月板失稳术（destabilization of the medial meniscus，DMM）术后8、12周2个时间点分层，每个时间点下使用随机数字表法设4组（

=5）：22 ℃假手术（22 ℃ Sham）组、4 ℃假手术（4 ℃ Sham）组、22 ℃ DMM组和4 ℃ DMM组。DMM术后2周，4 ℃ Sham与4 ℃ DMM组每日置于湿度（50±5）%、4 ℃低温舱暴露12 h，持续至相应终点；22 ℃ Sham与22 ℃ DMM组常规常温环境饲养。在干预8、12周时进行以下评估：①行为学测试：采用CatWalk系统量化步态参数，双足平衡测试评估肢体承重能力，旷场实验记录自发活动距离与时间，并在体测定股四头肌单收缩力（twitch）、强直收缩力（tetanus）及力-频率曲线（force-frequency curve）。②组织病理学分析：取股四头肌与膝关节组织，经石蜡包埋、切片后行HE染色和番红O-固绿染色，评估滑膜炎症细胞浸润、软骨表面完整性及国际骨关节炎研究学会（osteoarthritis research society international， OARSI）评分，同时通过Masson三色染色观察肌纤维胶原沉积。③分子检测：采用免疫荧光技术以Dystrophin抗体标记肌纤维边界并计算横截面积，免疫组化法检测滑膜组织中IL-1β、TNF-α的阳性表达水平。

结果

①小鼠行为学表现异常。与22 ℃ DMM组相比，4 ℃ DMM组在8、12周2个时间点均呈现显著加重的功能障碍：a.步态协调性丧失，8周时右后肢相对站立相时间降低0.113（

0.001）、足迹面积降低0.102（

0.05）、摆动相时间增加0.115（

0.05）、单肢站立时间降低0.146（

0.01）；至12周上述异常持续存在，足迹面积差异扩大至0.154（

0.05），摆动相时间仍维持0.113的升高幅度（

0.05）。b.承重能力衰退，8周时右足承重占比降低2.777%（

0.001），12周时降低程度进一步扩大至5.156%（

0.000 1）。c.自发活动抑制，8周时总活动距离减少1 069 cm（

0.000 1），12周时仍减少429.3 cm（

0.05）。②关节组织病理损伤加剧。寒冷暴露协同DMM手术显著加重滑膜炎症与软骨破坏：a.滑膜病变，4 ℃ DMM组相较22 ℃ DMM组在8周时滑膜病理评分增加2.133分（

0.01），12周时增至2.833分（

0.001），提示炎症反应持续升级。b.软骨退变，4 ℃ DMM组相较22 ℃ DMM组在8周时OARSI最大评分升高1.000分（

0.05）、总评分升高2.000分（

0.01）；12周时最大评分仍有0.750分的升高趋势，总评分维持2.000分的差异趋势。c.促炎因子表达上调，4 ℃ DMM组相较22 ℃ DMM组，滑膜IL-1β相对表达面积在8周和12周分别增加1.047%（

0.05）和1.892%（

0.05）；TNF-α表达面积较同期分别增加3.850%（

0.000 1）和3.806%（

0.0001）。③骨骼肌结构与收缩功能复合性损伤。寒冷干预导致股四头肌出现肌肉萎缩、力学性能衰退及纤维化重塑三重病理改变：a.肌力储备耗竭，Twitch在8周和12周分别降低34.77 mN·m/kg（

0.01）和52.87 mN·m/kg（

0.05）；Tetanus同期分别降低115.0 mN·m/kg（

0.05）和138.3 mN·m/kg（

0.000 1），Force-frequency curve下移。b.肌萎缩，股四头肌质量比在8周和12周分别降低0.076%（

0.05）和0.102%（

0.000 1）；肌纤维横截面积（cross-sectional area，CSA）同期分别减少261.3 μm²（

0.05）和233.5 μm²（

0.01），小直径肌纤维比例增高。c.纤维化沉积，肌组织胶原纤维相对面积在8周和12周分别增加4.072%（

0.01）和2.238%（

0.05），提示细胞外基质异常重构。

结论

高寒环境不仅可直接加剧骨关节炎的滑膜炎症与软骨退变，还能通过诱导股四头肌萎缩、肌力下降及纤维化等，进一步加剧关节结构与功能的恶化。

Abstract

Objective

To investigate the impact of a high-altitude and cold environment on skeletal muscle function and the pathological processes of osteoarthritis (OA)

to elucidate the interaction mechanisms between skeletal muscle atrophy

fibrosis

and joint degeneration under cold condition

aiming to found a theoretical basis for the health protection of the musculoskeletal system in military personnel stationed in high-altitude cold regions.

Methods

Destabilization of the medial meniscus (DMM) was established on C57BL/6 mice (11 weeks old)

by cutting the attaching point at the anterior intercondylar region where anterior cruciate ligament blends with the medial meniscus. Forty male C57BL/6 mice (11 weeks old) were stratified by 2 postoperative time points (8 and 12 weeks). At each time point

the mice were divided randomly divided into 4 groups

=5):22 ℃ sham operation (22 ℃ Sham)

4 ℃ sham operation (4 ℃ Sham)

22 ℃ DMM

and 4 ℃ DMM. From 2 weeks after DMM modelling

the 4 ℃ Sham and 4 ℃ DMM groups were placed in a cold chamber [4 ℃

humidity (50±5)%

]

for 12 h per day until the respective endpoint

meanwhile

the 22 ℃ Sham and 22 ℃ DMM groups were kept at room temperature. At 8 and 12 weeks after intervention

the following assessments were carried out:① Behavioral tests:Gait parameters were quantified using the CatWalk system;Limb load-bearing capacity was evaluated with bipedal balance test;Spontaneous activity distance and time were recorded in the open field test;Twitch force and tetanic force in the quadriceps were measured

and the force-frequency curve was plotted. ② Histopathological analysis:Quadriceps and knee joint tissues were harvested

embedded in paraffin

sectioned and stained with HE and safranin O-fast green to assess synovial inflammatory cell infiltration

cartilage surface integrity

and OARSI score from Osteoarthritis Research Society International System. Additionally

Masson’s trichrome staining was applied to observe collagen deposition in muscle fibers. ③ Molecular detection:Immunofluorescence assay for dystrophin antibody was used to label muscle fiber boundaries and calculate cross-sectional area;Immunohistochemistry assay was employed to determine the expression levels of IL-1β and TNF-α in synovial tissue.

Results

① Progressive deterioration of behavioral function:Compared with the 22 ℃ DMM group

the 4 ℃ DMM group exhibited significantly exacerbated functional impairments at both 8 and 12 weeks after intervention

in a time-dependent worsening trend. a. Loss of gait coordination: At 8

weeks

the relative stance phase time of the right hindlimb was shorten by 0.113 (

0.001)

print area was reduced by 0.102 (

0.05)

swing phase time was extended by 0.115 (

0.05)

and single-limb stand time was prolonged by 0.146 (

0.01). These abnormalities still existed at 12 weeks

with the difference of print area expanding to 0.154 (

0.05) and that of swing phase time maintaining an elevated magnitude of 0.113 (

0.05). b. Decline in weight-bearing capacity:Percentage of right paw weight-bearing was decreased by 2.777% at 8 weeks (

0.001)

with the deficit further expanding to 5.156% at 12 weeks (

0.000 1). c. Suppression of spontaneous activity:Total locomotor distance was decreased by 1 069 cm at 8 weeks (

0.000 1) and remained reduced by 429.3 cm at 12 weeks (

0.05). ② Exacerbation of joint histopathological damage:Cold exposure combined with DMM surgery significantly aggravated synovial inflammation and cartilage destruction. a. Synovial pathology:The 4 ℃ DMM group displayed increased synovial pathological score of 2.133 at 8 weeks (

0.01) and then 2.833 at 12 weeks (

0.001) relative to the 22 ℃ DMM group

indicating a sustained inflammatory response. b. Cartilage degeneration:The 4 ℃ DMM group showed the maximum score of OARSI elevated by 1.000 (

0.05) and total score by 2.000 (

0.01) at 8 weeks

while

at 12 weeks

the maximum score remained elevated by 0.750

and the total score maintained a differential trend of 2.000. c. Upregulation of pro-inflammatory factors:The synovial expression area of IL-1β in the 4 ℃ DMM group was increased by 1.047% (

0.05) and 1.892% (

0.05) at 8 and 12 weeks

respectively

and that of TNF-α expression was increased by 3.850% (

0.000

1) and 3.806% (

0.000 1)

separately at the same time points. ③ Composite impairment of skeletal muscle structure and contractile function:Cold intervention induced triple pathological changes in quadriceps encompassing atrophy

mechanical performance decline

and fibrotic remodeling. a. Depletion of muscular force reserve:Twitch force was decreased by 34.77 mN·m/kg (

0.01) and 52.87 mN·m/kg (

0.05) at 8 and 12 weeks

respectively;Tetanus force was reduced by 115.0 mN·m/kg (

0.05) and 138.3 mN·m/kg (

0.000 1) at the same time points

with a downward shift of the force-frequency curve. b. Muscle atrophy:The mass ratio of quadriceps was decreased by 0.076% (

0.05) and 0.102% (

0.000 1)

and the muscle fiber cross-sectional area (CSA) was reduced by 261.3 μm² (

0.05) and 233.5 μm² (

0.01) at 8 and 12 weeks

respectively

accompanied with an increased proportion of small-diameter fibers. c. Fibrotic deposition:Relative collagen fiber area in muscle tissue was increased by 4.072% (

0.01) and 2.238% (

0.05) at 8 and 12 weeks

respectively

suggesting abnormal extracellular matrix remodeling.

Conclusion

High-altitude cold environment not only directly aggravates synovial inflammation and cartilage degeneration in OA but also further compromises joint structure and function by inducing quadriceps atrophy

reduced muscle strength

and fibrosis.

关键词

Keywords

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