Obesity and type 2 diabetes (T2D) have become global health issues that severely affect human health. Impaired insulin sensitivity and glucose utilization in skeletal muscle play a causal role in the development of T2D. In the meantime, obesity and T2D are often associated with decreased muscle regeneration capacity and muscle weakness. These muscle complications further disrupt skeletal muscle energy metabolism and accelerate disease progression. However, the molecular pathways underlying obesity- and T2D-induced attenuation of muscle regeneration and myopathy remain unclear.

On June 7, the research team led by Prof. MENG Zhuoxian at the Zhejiang University School of Medicine published a research article titled “Myofiber Baf60c controls muscle regeneration via modulating Dkk3-mediated paracrine signaling”in the Journal of Experimental Medicine, elaborating a new intramuscular paracrine signaling pathway in controlling muscle regeneration, and its role in obesity- and T2D-induced myopathy.

The study started with the observations that muscle-specific knockout of Baf60c (BcMKO) led to severe regeneration defects in cardiotoxin (CTX)-induced acute muscle injury model: increased muscle weight loss, decreased regenerated area, and diminished muscle contraction force (Figure 1). In contrast, muscle-specific Baf60c transgene markedly promoted muscle regeneration.

Figure 1: Skeletal myofiber-specific inactivation of Baf60c impairs muscle regeneration

Through transcriptomic analysis and functional validation, the authors then identified Dkk3, a muscle-secreted factor, as the downstream mediator of Baf60c in regulating muscle regeneration. At the mechanism level, researchers found that Baf60c physically interacts with transcription factor Six4 to synergistically suppress Dkk3 gene expression in muscle cells.

Notably, Baf60c was down-regulated in the skeletal muscles of obese and diabetic mice and humans, leading to a significant upregulation of Dkk3 in skeletal muscle and an elevation of Dkk3 protein levels in the plasma. Researchers also observed a strong positive correlation between circulating Dkk3 levels and human body mass index (BMI). Further animal experiments revealed that Dkk3 knockdown significantly reversed obesity-induced muscle regeneration dysfunction in mice. These data indicate that the dysregulation of the BAF60c-Dkk3 axis may play an important role in the pathogenesis of impaired muscle stem cell function and reduced regenerative capacity in obese and diabetic humans.

Figure 2: Baf60c-dependent epigenetic signaling in myofibers regulates muscle regeneration through Dkk3-mediated paracrine signaling

In summary, this study identified Dkk3 as a downstream target of Baf60c in skeletal myofibers mediating its effects on muscle reparative capacity and contractile function through paracrine signaling to muscle stem cells (Figure 2). This work extends our understanding of the epigenetic mechanism from intracellular to intercellular and interorgan levels, elucidating the epigenetic mechanism of tissue homeostasis and energy metabolism and its significance in the occurrence and development of obesity and T2D. This study provides evidence suggesting that, besides providing a “habitat” for muscle stem cells, mature myofibers also actively regulate muscle stem cell regenerative capacity and tissue homeostasis through paracrine signaling.

“This is an unexpected discovery,” says Dr. MENG Zhuoxian. Our findings help elucidate the molecular mechanism of diabetic myopathy and provide a potential new biomarker and therapeutic target for the diagnosis and treatment of obesity- and diabetes-associated muscle diseases.

Source: The research team led by Dr. MENG Zhuoxian