MondoA Is Required for Normal Myogenesis and Regulation of the Skeletal Muscle Glycogen Content in Mice

Abstract

Background: Skeletal muscle is the largest tissue in the human body, and it plays a major role in exerting force and maintaining metabolism homeostasis. The role of muscle transcription factors in the regulation of metabolism is not fully understood. Mon-doA is a glucose-sensing transcription factor that is highly expressed in skeletal muscle. Previous studies suggest that MondoA can influence systemic metabolism homeostasis. However, the function of MondoA in the skeletal muscle remains unclear. Methods: We generated muscle-specific MondoA knockout (MAKO) mice and analyzed the skeletal muscle morphology and glycogen content. Along with skeletal muscle from MAKO mice, C2C12 myocytes transfected with small interfering RNA against MondoA were also used to investigate the role and potential mechanism of MondoA in the development and glycogen metabolism of skeletal muscle. Results: MAKO caused muscle fiber atrophy, reduced the proportion of type II fibers compared to type I fibers, and increased the muscle glycogen level. MondoA knockdown inhibited myoblast proliferation, migration, and differentiation by inhibiting the phosphatase and tensin homolog (PTEN)/phosphoinositide 3-kinase (PI3K)/Akt pathway. Further mechanistic experiments revealed that the increased muscle glycogen in MAKO mice was caused by thioredoxin-interacting protein (TXNIP) downregulation, which led to upregulation of glucose transporter 4 (GLUT4), potentially increasing glucose uptake. Conclusion: MondoA appears to mediate mouse myofiber development, and MondoA decreases the muscle glycogen level. The findings indicate the potential function of MondoA in skeletal muscle, linking the glucose-related transcription factor to myogenesis and skeletal myofiber glycogen metabolism.

Normal and Neoplastic Growth Suppression by The Extended Myc Network

“…Originally identified by yeast two-hybrid screening as a bHLH-ZIP binding partner for Mlx, MondoA was quickly determined to be a paralog of ChREBP, albeit with a wider tissue distribution pattern including particularly high expression in skeletal muscle, where it is required for normal development [33,34,77,78,370]. Like ChREBP, MondoA is regulated by glucose and G6P in a manner that utilizes a similar N-terminal GSM module that is also dependent upon 14-3-3 protein interactions [41,371].…”

The Role of Mondo Family Transcription Factors in Nutrient-Sensing and Obesity

“…As a direct and glucose-responsive target of MondoA, TXNIP is upregulated when G6P level increases and concomitantly restricts glucose absorption, thus providing a negative feedback loop to prevent energy overload. Mechanisms underlying inhibition of glucose uptake regulated by TXNIP include the suppression of glucose transporter (GLUT) expression, GLUT vesicle transport and insulin signaling ( 44 , 62 – 64 ). Moreover, MondoA enhances glycogen synthesis by activating the transcription of phosphoprotein phosphatase 1 regulatory subunit 3A (PPP1R3A), phosphoprotein phosphatase 1 regulatory subunit 3B (PPP1R3B) and genes encoding the glycogen targeting subunits of protein phosphatase 1 (PP1) for promoting glycogen synthesis ( 65 , 66 ).…”

“…Moreover, MondoA enhances glycogen synthesis by activating the transcription of phosphoprotein phosphatase 1 regulatory subunit 3A (PPP1R3A), phosphoprotein phosphatase 1 regulatory subunit 3B (PPP1R3B) and genes encoding the glycogen targeting subunits of protein phosphatase 1 (PP1) for promoting glycogen synthesis ( 65 , 66 ). Muscle-specific MondoA knockout decreases glycogen level in the skeletal muscle of mice ( 62 ) ( Table 1 ). Hence, under physiological conditions, glucose homeostasis is maintained by the downstream effects of MondoA activation.…”

“…MondoA is expressed predominantly in skeletal muscle which makes up ~40% of body weight and is responsible for ~80% of glucose uptake ( 62 , 85 ). Therefore, as a transcriptional factor required for maintaining body homeostasis, MondoA plays a crucial part in inter-organ metabolic crosstalk.…”

“…Moreover, SBI-477, a potent inhibitor of MondoA, alleviates muscle triglyceride levels and hepatic steatosis, thereby improving glucose tolerance in mice on a high-fat diet ( 45 ). However, the significant role of MondoA in skeletal muscle development has been recently revealed in mice ( 62 ). Therefore, in the development of MondoA as a novel therapeutic target, the timing for treatment is critical and the risk of interfering with normal myogenesis needs to be avoided.…”