Department of Metabolism and Endocrinology, Akita University Graduate School of Medicine, Akita, Japan.
Department of Endocrinology, Diabetes and Metabolism, Fujita Health University, Toyoake, Japan.
J Cachexia Sarcopenia Muscle. 2023 Dec;14(6):2703-2718. doi: 10.1002/jcsm.13346. Epub 2023 Oct 27.
Intramuscular adipose tissue (IMAT) formation derived from muscle fibro-adipogenic progenitors (FAPs) has been recognized as a pathological feature of sarcopenia. This study aimed to explore whether genetic and pharmacological gastric inhibitory polypeptide (GIP) receptor antagonism suppresses IMAT accumulation and ameliorates sarcopenia in mice.
Whole body composition, grip strength, skeletal muscle weight, tibialis anterior (TA) muscle fibre cross-sectional area (CSA) and TA muscle IMAT area were measured in young and aged male C57BL/6 strain GIP receptor (Gipr)-knockout (Gipr ) and wild-type (Gipr ) mice. FAPs isolated from lower limb muscles of 12-week-old Gipr mice were cultured with GIP, and their differentiation into mature adipocytes was examined. Furthermore, TA muscle IMAT area and fibre CSA were measured in untreated Gipr mice and GIP receptor antagonist-treated Gipr mice after glycerol injection into the TA muscles.
Body composition analysis revealed that 104-week-old Gipr mice had a greater proportion of lean tissue mass (73.7 ± 1.2% vs. 66.5 ± 2.7%, P < 0.05 vs. 104-week-old Gipr mice) and less adipose tissue mass (13.1 ± 1.3% vs. 19.4 ± 2.6%, P < 0.05 vs. 104-week-old Gipr mice). Eighty-four-week-old Gipr mice exhibited increases in grip strength (P < 0.05), weights of TA (P < 0.05), soleus (P < 0.01), gastrocnemius (P < 0.05) and quadriceps femoris (P < 0.01) muscles, and average TA muscle fibre CSA (P < 0.05) along with a reduction in TA muscle IMAT area assessed by the number of perilipin-positive cells (P < 0.0001) compared with 84-week-old Gipr mice. Oil Red O staining analysis revealed 1.6- and 1.7-fold increased adipogenesis in muscle FAPs cultured with 10 and 100 nM of GIP (P < 0.01 and P < 0.001 vs. 0 nM of GIP, respectively). Furthermore, both untreated Gipr mice and GIP receptor antagonist-treated Gipr mice for 14 days after glycerol injection into the TA muscles at 12 weeks of age showed reduced TA muscle IMAT area (1.39 ± 0.38% and 2.65 ± 0.36% vs. 6.54 ± 1.30%, P < 0.001 and P < 0.01 vs. untreated Gipr mice, respectively) and increased average TA muscle fibre CSA (P < 0.01 and P < 0.05 vs. untreated Gipr mice, respectively).
GIP promotes the differentiation of muscle FAPs into adipocytes and its receptor antagonism suppresses IMAT accumulation and promotes muscle regeneration. Pharmacological GIP receptor antagonism may serve as a novel therapeutic approach for sarcopenia.
肌内脂肪组织（IMAT）来源于肌肉纤维脂肪祖细胞（FAPs），已被认为是肌肉减少症的病理特征。本研究旨在探讨遗传和药理学胃抑制肽（GIP）受体拮抗是否抑制 IMAT 积累并改善小鼠的肌肉减少症。
在年轻和老年雄性 C57BL/6 品系 GIP 受体（Gipr）敲除（Gipr）和野生型（Gipr）小鼠中测量全身成分、握力、骨骼肌重量、比目鱼肌（TA）肌肉纤维横截面积（CSA）和 TA 肌肉 IMAT 面积。从 12 周龄 Gipr 小鼠的下肢肌肉中分离出 FAPs，并用 GIP 培养，并检查其向成熟脂肪细胞的分化。此外，在甘油注射到 TA 肌肉后，在未经治疗的 Gipr 小鼠和 GIP 受体拮抗剂治疗的 Gipr 小鼠中测量 TA 肌肉 IMAT 面积和纤维 CSA。
身体成分分析显示，104 周龄 Gipr 小鼠具有更大比例的瘦组织质量（73.7±1.2%比 66.5±2.7%，P<0.05 比 104 周龄 Gipr 小鼠）和更少的脂肪组织质量（13.1±1.3%比 19.4±2.6%，P<0.05 比 104 周龄 Gipr 小鼠）。84 周龄 Gipr 小鼠的握力增加（P<0.05），TA（P<0.05）、比目鱼肌（P<0.01）、腓肠肌（P<0.05）和股四头肌（P<0.01）肌肉的重量以及 TA 肌肉纤维 CSA 的平均增加（P<0.05），同时通过脂联素阳性细胞数量评估的 TA 肌肉 IMAT 面积减少（P<0.0001）与 84 周龄 Gipr 小鼠相比。油红 O 染色分析显示，用 10 和 100 nM 的 GIP 培养的肌肉 FAPs 的成脂分化增加了 1.6-和 1.7 倍（P<0.01 和 P<0.001 比 0 nM 的 GIP）。此外，甘油注射到 TA 肌肉后未经治疗的 Gipr 小鼠和 GIP 受体拮抗剂治疗的 Gipr 小鼠 14 天，TA 肌肉 IMAT 面积减少（1.39±0.38%和 2.65±0.36%比 6.54±1.30%，P<0.001 和 P<0.01 比未经治疗的 Gipr 小鼠），TA 肌肉纤维 CSA 平均增加（P<0.01 和 P<0.05 比未经治疗的 Gipr 小鼠）。
GIP 促进肌肉 FAP 向脂肪细胞分化，其受体拮抗抑制 IMAT 积累并促进肌肉再生。药理学 GIP 受体拮抗可能是肌肉减少症的一种新的治疗方法。
