Gastric inhibitory polypeptide receptor antagonism suppresses intramuscular adipose tissue accumulation and ameliorates sarcopenia

Abstract

Abstract Background 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. Methods 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. Results 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). Conclusions 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.

Keywords

• aging
• fibro‐adipogenic progenitors
• GIP receptor
• intramuscular adipose tissue
• sarcopenia