ChREBP deficiency aggravates diabetic sarcopenia by disrupting glucose signaling: a novel mouse model of muscle atrophy

Diabetes is an increasingly prevalent global disease and is often accompanied by sarcopenia, particularly in older adults. While insulin resistance is a well-known contributor to muscle loss in diabetes, the role of glucose signaling in diabetic skeletal muscle atrophy, particularly under insulin-deficient conditions, remains poorly understood. This study aimed to elucidate the pathophysiological role of the carbohydrate-responsive element-binding protein (ChREBP), a glucose-sensing transcription factor encoded by the Chrebp gene in mice, in diabetic sarcopenia by generating Chrebp-deficient, insulin-deficient Ins2^Akita/+ mice. We evaluated Chrebp^+/+, Chrebp^−/−, Ins2^Akita/+/Chrebp^+/+, and Ins2^Akita/+/Chrebp^−/− mice for muscle strength, endurance, survival, body composition, and muscle histology. Skeletal muscles were analyzed for gene expressions related to anabolic and catabolic pathways. We found that Ins2^Akita/+/Chrebp^−/− mice exhibited significant reductions in body weight, grip strength, survival, and skeletal muscle mass – particularly in the tibialis anterior, soleus, gastrocnemius, and quadriceps – compared to Ins2^Akita/+ controls, despite similar hyperglycemia. Histological analysis revealed a smaller mean muscle fiber size and reduced cross-sectional area of type 2A and 2B fibers, without changes in fiber-type composition. Furthermore, Igf-1 expression was suppressed, while the atrophy marker Fbxo32/Atrogin-1 was upregulated. These findings demonstrate that Chrebp deletion exacerbates muscle atrophy and frailty in insulin-deficient mice, underscoring a key role for ChREBP-mediated glucose signaling in maintaining muscle mass under diabetic conditions. The Ins2^Akita/+/Chrebp^−/− model provides a valuable platform for exploring diabetic sarcopenia mechanisms and potential therapeutic targets.