Insulin Deficiency Exacerbates Muscle Atrophy and Osteopenia in Chrebp Knockout Mice

Type 1 diabetes mellitus is a major risk factor for both sarcopenia and osteoporosis, primarily due to the body's inability to utilize glucose as a result of insulin deficiency. Impairments in insulin and glucose signaling can accelerate the decline in muscle and bone health. To investigate this interaction, we examined whether insulin deficiency exacerbates muscle and bone deterioration in Chrebp knockout (KO) mice. Male wild-type (WT) and KO mice, aged 18 weeks, were intraperitoneally treated with 200 mg/kg BW streptozotocin (STZ), which selectively destroys pancreatic beta cells, thereby inducing insulin deficiency. Two weeks after STZ administration, compared with STZ-treated WT mice, STZ-treated KO mice presented significantly greater reductions in body weight and gastrocnemius muscle weight (BW: WT-vehicle vs. WT-STZ; 2.58 [-1.23, 6.39] (p = 0.21); KO-vehicle vs. KO-STZ: 8.03 [5.23, 10.82]; GA muscle: WT vehicle vs. WT STZ: 0.084 [0.047, 0.12], p < 0.0001; KO vehicle vs. KO STZ: 0.084, [0.047, 0.12], p < 0.0001). The decrease in grip strength caused by STZ administration was greater in the KO mice than in the WT mice (mean differences [95% CIs]: WT vehicle-WT STZ, 49.6. [0.9, 98.4], p = 0.046; WT STZ-KO STZ: 71.40 [29.1, 113.7], p = 0.0059; KO vehicle-KO STZ: 84.3 [51.9, 116.8], p = 0.0003). Consistent with these findings, STZ administration reduced IGF-1 expression and increased atrogin mRNA levels, with the highest levels in STZ-treated KO mice. In skeletal muscle, the changes in IGF-1 and Atrogen induced by STZ administration were significantly greater in the KO group than in the WT group (IGF-1: WT vehicle-WT STZ: 0.19 [-0.072, 0.46], p = 0.17; KO vehicle-KO STZ: 0.79 [0.53, 1.06], p < 0.0001; Atrogen: WT vehicle-WT STZ: -2.7 [-3.01, -2.29], p < 0.0001; KO vehicle-KO STZ: -3.35 [-3.71, -2.99], p < 0.0001). The BMD in the Chrebp-deficient group was greater than that in the wild-type group (WT vehicle-KO vehicle: -5.2 [-8.4, -1.9], p = 0.0014); however, the administration of STZ significantly decreased the BMD only in the KO group (WT vehicle-WT STZ: p = 0.45, KO vehicle-KO STZ: 7.2 [3.9, 10.4], p < 0.0001). These results suggest that Chrebp deficiency combined with insulin deficiency aggravates sarcopenia and osteoporosis risk. Therefore, insulin and glucose signals are important for maintaining muscle and bone mass and function. However, further studies are needed to elucidate the mechanisms by which ChREBP deletion and insulin deficiency cause osteosarcopenia.