A Newly Discovered lncRNA May Explain The Loss of Muscle Mass in People with Type 2 Diabetes

Long noncoding RNAs (lncRNAs) make up a significant portion of the genome and encompass a diverse class of RNA molecules that are not translated into proteins. As important regulators of cell and tissue function, lncRNAs have been shown to be closely associated with the development and progression of metabolic diseases. Type 2 diabetes is a metabolic disease that poses an increasing burden on public health. The etiology of type 2 diabetes is complex, involving multiple tissues leading to glucose homeostasis disorders.

Although studies have shown that some lncRNAs can regulate glucose and lipid metabolism in the liver and adipose tissue, as well as the functional properties of pancreatic islets, their role in skeletal muscle is still unclear. Skeletal muscle accounts for approximately 50% of body weight. As the main site of insulin-stimulated glucose metabolism, insulin dysfunction in skeletal muscle often occurs early in the pathological process of type 2 diabetes. In addition, type 2 diabetes is associated with decreased muscle mass, which may be aggravated by GLP-1 receptor agonists as a weight loss therapy.

In a new study, researchers from Karolinska Institutet in Sweden, Institut Mondor in France and Inland University in the Netherlands have discovered a previously unknown molecule. This molecule, called TMEM9B-AS1, is a long noncoding RNA (lncRNA) that plays an important role in regulating cell function. This discovery may explain why people with type 2 diabetes often experience muscle weakness and muscle loss - a condition that has a significant impact on quality of life and overall health. The relevant research results were published in the journal Sciences Advances.

While searching for lncRNAs associated with insulin resistance, the researchers found that the expression of lncRNA TMEM9B-AS1 was downregulated in skeletal muscle of male patients with type 2 diabetes. To clarify the role of this differentially expressed lncRNA in metabolic processes, they provided evidence that TMEM9B-AS1 is necessary for protein synthesis and promotes the stability of MYC mRNA through physical interaction with the RNA binding protein IGF2BP1, thereby regulating ribosome biogenesis.

Figure 1. TMEM9B-AS1 regulates MYC mRNA stability through physical interaction with RNA-binding IGF2BP1 in human myotubes. (Sen I, et al., 2025)

This interaction is essential for ribosome biogenesis and protein synthesis in myotubes, as well as muscle contraction and the expression of structural proteins. Therefore, maintaining adequate levels of TMEM9B-AS1 could mitigate impairments in skeletal muscle mass and function and could be a potential target for improving metabolic health and physical performance.

"Our study shows that TMEM9B-AS1 supports the stability of the MYC gene, which is a key gene driving the production of ribosomes (protein manufacturing factories)," says Ilke Sen, first author of the paper and affiliated researcher at the Department of Physiology and Pharmacology at Karolinska Institutet. "In the absence of this RNA molecule, MYC becomes unstable and muscle cells lose the ability to maintain normal protein production. This could help explain the muscle degeneration commonly seen in patients with metabolic diseases."

Reference

Sen I, et al. Down-regulation of human-specific lncRNA TMEM9B-AS1 in skeletal muscle of people with type 2 diabetes affects ribosomal biogenesis. Science Advances, 2025, 11(28): eads4371.