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. 2024 Apr 1;14(1):7670.
doi: 10.1038/s41598-024-57727-2.

Mechanism of muscle atrophy in a normal-weight rat model of type 2 diabetes established by using a soft-pellet diet

Sayaka Akieda-Asai  1 , Hao Ma  2 , Wanxin Han  2 , Junko Nagata  3 , Fumitake Yamaguchi  2   4 , Yukari Date  5
Affiliations

Mechanism of muscle atrophy in a normal-weight rat model of type 2 diabetes established by using a soft-pellet diet

Sayaka Akieda-Asai et al. Sci Rep. .

Abstract

Dietary factors such as food texture affect feeding behavior and energy metabolism, potentially causing obesity and type 2 diabetes. We previously found that rats fed soft pellets (SPs) were neither hyperphagic nor overweight but demonstrated glucose intolerance, insulin resistance, and hyperplasia of pancreatic β-cells. In the present study, we investigated the mechanism of muscle atrophy in rats that had been fed SPs on a 3-h time-restricted feeding schedule for 24 weeks. As expected, the SP rats were normal weight; however, they developed insulin resistance, glucose intolerance, and fat accumulation. In addition, skeletal muscles of SP rats were histologically atrophic and demonstrated disrupted insulin signaling. Furthermore, we learned that the muscle atrophy of the SP rats developed via the IL-6-STAT3-SOCS3 and ubiquitin-proteasome pathways. Our data show that the dietary habit of consuming soft foods can lead to not only glucose intolerance or insulin resistance but also muscle atrophy.

Keywords: Diabetes; Eating habits; Energy metabolism; Glucose metabolism; Muscle atrophy; Soft food.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
Body weight and caloric intake. (A) Body weight and (B) caloric intake of rats fed soft pellets (SPs) or control pellets (CPs) (n = 16 per group).
Figure 2
Figure 2
Glucose, insulin, and HOMA-IR. (A) Blood glucose levels assessed through glucose tolerance testing (GTT) of rats fed SPs or CPs for 16 weeks. (B) Plasma insulin levels assessed through GTT. (C) Blood glucose, plasma insulin level, and HOMA-IR were assessed in overnight-fasted rats fed SPs or CPs for 24 weeks. n = 6 per group. *P < 0.05, **P < 0.01, ***P < 0.01 vs. rats fed CPs. AUC, area under the curve.
Figure 3
Figure 3
Subcutaneous and visceral fat proportions and lipid content in liver and blood of rats fed SPs or CPs for 24 weeks. (A) Computed tomographic images of rats fed SPs or CPs, indicating areas of subcutaneous (yellow) and visceral (red) fat and muscle (blue). (B) Percentages of subcutaneous fat, visceral fat, and lean mass as estimated from images taken from the proximal end of L1 to the distal end of L6. n = 6 per group. (C–E) Triacylglycerol content in (C) liver, (D) gastrocnemius muscle, and (E) soleus muscle. (F) Plasma triglyceride concentration. n = 16 per group. (G) Plasma triglyceride levels after feeding. n = 5 per group. *P < 0.05, ***P < 0.001 vs. rats fed CPs.
Figure 4
Figure 4
Amounts of phosphorylated (p-) Akt and GLUT4 in the skeletal muscle of rats fed SPs or CPs for 24 weeks. Quantities of p-Akt after insulin injection or without insulin treatment in (A) gastrocnemius muscle and (B) soleus muscle. The GLUT4 level in the plasma membrane (PM) fractions from (C) gastrocnemius muscle and (D) soleus muscle was assessed after insulin injection or without insulin treatment. The original gel blots are presented in the Supplementary Fig. S4. n = 6 per group. *P < 0.05, ***P < 0.001 vs. rats fed CPs or SPs without insulin treatment. +++P < 0.001 vs. rats fed CPs and treated with insulin.
Figure 5
Figure 5
Cross-sectional area (CSA) of muscle fiber and assessment of protein degradation pathways in the skeletal muscle of rats fed SPs or CPs for 24 weeks. (A,B) Muscle fiber CSA in (A) gastrocnemius muscle and (B) soleus muscle. (C,E) mRNA levels of enzymes in the ubiquitin–proteasome pathway in (C) gastrocnemius muscle and (E) soleus muscle. (D,F) mRNA levels of enzymes in the autophagy–lysosome pathway in (D) gastrocnemius muscle and (F) soleus muscle. Bar, 100 μM. n = 16 per group. *P < 0.05, **P < 0.01, ***P < 0.001 vs. rats fed CPs.
Figure 6
Figure 6
Proinflammatory factors and the IL-6–STAT3–SOCS3 pathway in the skeletal muscle of rats fed SPs or CPs for 24 weeks. (A,B) Proinflammatory factors in (A) gastrocnemius muscle and (B) soleus muscle. n = 16 per group. (C) Plasma IL-6 levels. n = 16 per group. (D,E) IL-6 protein levels in (D) gastrocnemius muscle and (E) soleus muscle. n = 10 per group. (F) IL-6 mRNA levels in L6 myocytes after treatment with glucose or free fatty acids (FFA) for 24 h. (G) IL-6 mRNA levels in isolated satellite cells after treatment with glucose or FFA for 24 h. n = 5 per group. (H,J) Amount of p-Stat3 in (H) gastrocnemius muscle and (J) soleus muscle. The original gel blots are presented in the Supplementary Fig. S5. (I,K) SOCS3 mRNA levels in (I) gastrocnemius muscle and (K) soleus muscle. n = 16 per group. *P < 0.05 vs. rats fed CPs. ***P < 0.001 vs. cells treated with 5 mM glucose.
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