Korean J Physiol Pharmacol.  2022 May;26(3):207-218. 10.4196/kjpp.2022.26.3.207.

The effect of fibroblast growth factor receptor inhibition on resistance exercise training-induced adaptation of bone and muscle quality in mice

• Cho S
• Lee H
• Lee HY
• Kim SJ
• Song W

• KMID: 2529403
• DOI: http://doi.org/10.4196/kjpp.2022.26.3.207

Abstract

Aging in mammals, including humans, is accompanied by loss of bone and muscular function and mass, characterized by osteoporosis and sarcopenia. Although resistance exercise training (RET) is considered an effective intervention, its effect is blunted in some elderly individuals. Fibroblast growth factor (FGF) and its receptor, FGFR, can modulate bone and muscle quality during aging and physical performance. To elucidate this possibility, the FGFR inhibitor NVP-BGJ398 was administrated to C57BL/6n mice for 8 weeks with or without RET. Treatment with NVPBGJ398 decreased grip strength, muscular endurance, running capacity and bone quality in the mice. FGFR inhibition elevated bone resorption and relevant gene expression, indicating altered bone formation and resorption. RET attenuated tibial bone resorption, accompanied by changes in the expression of relevant genes. However, RET did not overcome the detrimental effect of NVP-BGJ398 on muscular function. Taken together, these findings provide evidence that FGFR signaling may have a potential role in the maintenance of physical performance and quality of bone and muscles.

Keyword

Atrophy; Bone density; Exercise training; Fibroblast growth factor receptor; Muscle

Figure

• 

  Fig. 1 Effect of FGFR inhibition on body composition and physical performance. FGFR inhibitor treatment (NVP-BGJ398, 50 mg/kg b.w.) was administrated daily up to 8 weeks through oral gavage on Inh group (n = 7) while Sham group (n = 7) was treated with same amount of vehicle (PEG 300: glucose 5% 2:1 mix; n = 7). The b.w. were measured (A) weekly and (B) before sacrificed. Body composition analysis was taken before dissection and represented with (C) lean body mass and (D) body fat percentage of b.w. Physical performance test was conducted 48 h after intervention. General phenotype tests are such as (E) grip strength, (F) hanging and (G) treadmill exhaustion test. All values are presented as mean ± SEM. FGFR, fibroblast growth factor receptor; b.w., body weight. *p < 0.05, **p < 0.01.

• 

  Fig. 2 Effect of FGFR inhibition on bone quality and turnover markers. Micro/PET-CT mage scan was conducted after FGFR inhibitor (Inh) treatment. (A) Micro-CT scan image of representative animals from each group and summary statistics of averaged HU value. (B) PET-CT scan image of representative animals from each group and summary statistics of averaged SUV (g/ml). Bone turnover markers were measured with qRT-PCR. Gene expression level of (C) osteogenic genes (Osteocalcin, Runx2, and Alp) and (D) osteoclastogenic genes (Opg and Rankl) was normalized with Gapdh. All values are presented as mean ± SEM. FGFR, fibroblast growth factor receptor; PET-CT, positron emission tomography/computed tomography; HU, Hounsfield unit; SUV, standardized uptake values. *p < 0.05, **p < 0.01.

• 

  Fig. 3 Effect of FGFR inhibition on muscle quality and skeletal muscle atrophy markers. Muscle wet weight was adjusted with body weight (A) Soleus, Gastrocnemius, Tibialis anterior and Extensor digitorum longus muscle. (B) Relative grip strength was adjusted by total lower limb muscle mass to evaluate the muscle quality. (C) mRNA expression level of gastrocnemius muscle was measured Atrophy markers were measured with qRT-PCR. Gene expression level of Atrogin1, Murf1, and Foxo1 was normalized with Gapdh. All values are presented as mean ± SEM. FGFR, fibroblast growth factor receptor. *p < 0.05, **p < 0.01.

• 

  Fig. 4 Effect of RET during FGFR inhibition. Physical performance was tested after 8 weeks of ladder climbing exercise with FGFR inhibitor treatment: Sham-RET (PEG 300: glucose 5% 2:1 mix; n = 7) vs. Inh-RET (NVP-BGJ398, 50 mg/kg b.w.; n = 7). Body weight was measured (A) weekly and (B) before sacrificed. Body composition analysis was taken before dissection and represented with (C) lean body mass and (D) body fat percentage of b.w. Physical performance test was conducted 48 h after intervention. General phenotype tests are such as (E) grip strength, (F) hanging and (G) treadmill exhaustion test. All values are presented as mean ± SEM. RET, resistance exercise training; FGFR, fibroblast growth factor receptor; b.w., body weight. **p < 0.01.

• 

  Fig. 5 Effect of resistance exercise training during FGFR inhibition on bone quality and turnover markers. Micro/PET-CT mage scan was done after 8 weeks of ladder climbing exercise with FGFR inhibitor treatment. (A) Micro-CT scan image of representative animals from each group and summary statistics of averaged HU value. (B) PET-CT scan image of representative animals from each group and summary statistics of averaged SUV (g/ml). Bone turnover markers were measured with qRT-PCR. Gene expression level of (C) osteogenic genes (Osteocalcin, Runx2, and Alp) and (D) osteoclastogenic genes (Opg and Rankl) was normalized with GAPDH. All values are presented as mean ± SEM. FGFR, fibroblast growth factor receptor; RET, resistance exercise training; PET-CT, positron emission tomography/computed tomography; HU, Hounsfield unit; SUV, standardized uptake values. *p < 0.05.

• 

  Fig. 6 Effect of resistance exercise training during FGFR inhibition on muscle quality and skeletal muscle atrophy markers. Muscle wet weight adjusted with body weight (A) Soleus, Gastrocnemius, Tibialis anterior and Extensor digitorum longus muscle. (B) Relative grip strength was adjusted by total lower limb muscle mass to evaluate the muscle quality. (C) mRNA expression level of gastrocnemius muscle was measured Atrophy markers were measured with quantitative RT-PCR. Gene expression level of Atrogin1, Murf1, and Foxo1 was normalized with Gapdh. All values are presented as mean ± SEM. FGFR, fibroblast growth factor receptor; RET, resistance exercise training.**p < 0.01.

• 

  Fig. 7 Schematic diagrams of the blunted adaptation of resistance exercise training during FGFR inhibition. (A) RET generally provide beneficial effect on bone and muscle quality. (B) FGFR inhibition with NVP-BGJ398 altered bone and muscle quality detrimentally. (C) RET adaptation on bone and muscle were blunted with FGFR inhibition. However, elevated bone resorption was improved. FGFR, fibroblast growth factor receptor; RET, resistance exercise training.

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