Chen Ziyi, Xu Jiankun, Hu Peijie, Du Wanting, Chen Junjiang, Zhang Xiaotian, Zhou Wei, Gao Jiayang, Zhang Yuantao, Dai Bingyang, Nie Guangshuai, Hu Jun, Zhou Liangbin, Xu Shunxiang, Chan Hisao Chang, Cheung Wing-Hoi, Ruan Ye Chun, Qin Ling
Musculoskeletal Research Laboratory, Department of Orthopedics & Traumatology, The Chinese University of Hong Kong, Hong Kong, China.
Department of Biomedical Engineering, Faculty of Engineering, The Hong Kong Polytechnic University, Hong Kong, China.
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1):e13708. doi: 10.1002/jcsm.13708.
Regenerative capacity of skeletal muscles decreases with age. Deficiency in cystic fibrosis transmembrane conductance regulator (CFTR) is associated with skeletal muscle weakness as well as epithelial cell senescence. However, whether and how CFTR plays a role in skeletal muscle regeneration and aging were unclear.
Vastus lateralis biopsy samples from male and female human subjects (n = 23) of 7- to 86-year-old and gastrocnemii tissues from mice of 4- to 29-month-old were examined for CFTR expression. Skeletal muscle tissues or cultured myoblasts from mice carrying CFTR mutation (DF508) at 4- to 18-month-old were used for assessment of muscle mass, contractile force and regenerative capacity as well as myogenic and autophagy signalling. Overexpression of LC3-β, an autophagy mediator, was conducted to reverse myogenic defects in DF508 myoblasts. Adenoviruses containing CFTR gene or pharmaceuticals that enhance CFTR (VX809) were locally injected into the gastrocnemius or femoris quadricep to rescue age-related skeletal muscle defects in mice.
mRNA levels of CFTR in human vastus lateralis exhibited significantly negative correlations with age (r = -0.87 in males and -0.62 in females, p < 0.05). Gastrocnemius mRNA level of CFTR decreased by 77.7 ± 4.6% in 29-month-old wild-type mice compared to the 4-month-old. At 18-month-old, DF508 mice showed significantly reduced lean mass (by 35.6%), lower specific twitch force of the gastrocnemius (by 46.2%), decrease in fast/slow-twitch muscle isoform ratio as well as downregulation of myogenic (e.g., MYOD and MYOG) or autophagy/mitophagy (e.g., LC3-β) genes, compared to age-matched wild-types. Post-injury gastrocnemius regeneration was found impaired in DF508 mice. Myoblast cultures from DF508 mice showed defective myogenic differentiation, which was reversed by overexpressing LC3-β. In aged (> 15-month-old) mice, overexpressing CFTR or VX809 restored the expression of autophagy or myogenic genes, increased mitochondrial LC3-β level and improved skeletal muscle mass and function.
Age-related reduction in skeletal muscle expression of CFTR impairs autophagy and myogenesis, exacerbating skeletal muscle aging. Enhancing CFTR might be a potential treatment strategy for age-related skeletal muscle disorders.
骨骼肌的再生能力随年龄增长而下降。囊性纤维化跨膜传导调节因子（CFTR）缺乏与骨骼肌无力以及上皮细胞衰老有关。然而，CFTR是否以及如何在骨骼肌再生和衰老中发挥作用尚不清楚。
检测了7至86岁男性和女性人类受试者（n = 23）的股外侧肌活检样本以及4至29月龄小鼠的腓肠肌组织中的CFTR表达。使用4至18月龄携带CFTR突变（DF508）的小鼠的骨骼肌组织或培养的成肌细胞来评估肌肉质量、收缩力和再生能力以及肌源性和自噬信号传导。进行自噬介质LC3-β的过表达以逆转DF508成肌细胞中的肌源性缺陷。将含有CFTR基因的腺病毒或增强CFTR的药物（VX809）局部注射到腓肠肌或股四头肌中，以挽救小鼠与年龄相关的骨骼肌缺陷。
人类股外侧肌中CFTR的mRNA水平与年龄呈显著负相关（男性r = -0.87，女性r = -0.62，p < 0.05）。与4月龄相比，29月龄野生型小鼠腓肠肌中CFTR的mRNA水平下降了77.7±4.6%。在18月龄时，与年龄匹配的野生型相比，DF508小鼠的瘦体重显著降低（35.6%），腓肠肌的比目鱼肌特定抽搐力降低（46.2%），快/慢肌亚型比例下降，以及肌源性（如MYOD和MYOG）或自噬/线粒体自噬（如LC3-β）基因下调。发现DF508小鼠损伤后腓肠肌再生受损。来自DF508小鼠的成肌细胞培养物显示出有缺陷的肌源性分化，通过过表达LC3-β得以逆转。在老年（> 15月龄）小鼠中，过表达CFTR或VX809可恢复自噬或肌源性基因的表达，增加线粒体LC3-β水平，并改善骨骼肌质量和功能。
与年龄相关的骨骼肌中CFTR表达降低会损害自噬和肌生成，加剧骨骼肌衰老。增强CFTR可能是治疗与年龄相关的骨骼肌疾病的潜在策略。
