Impaired Muscle Gene Expression Linked to Type 2 Diabetes

Type-2 diabetes comes with a slew of health issues, but one complication that patients often endure is muscle weakness. Poor muscle function makes everyday tasks difficult and reduces activity, which in turn, makes the condition even worse. While exercise and diet can help maintain a patient’s mobility, more information is needed to address the underlying causes that lead to diabetic muscle damage.

Scientists at Lund University in Sweden have looked into this matter and have found evidence that one particular gene may be epigenetically impaired, contributing to muscle deterioration. The gene, simply known as VPS39, plays a role in skeletal muscle regeneration and maintenance. According to the study, it was found to be downregulated due to altered epigenetic mechanisms in individuals with type-2 diabetes (T2D). Their findings were published in the journal Nature Communications.

Insulin resistance and decreased muscle quality are hallmarks of T2D. Understanding how these two are correlated could no doubt help those living with the disease live healthier lives. With T2D, insulin production is impaired, leaving excess sugar in the blood. Because muscle tissue is poor at absorbing the glucose for fuel, it starts to deteriorate and loses function. 

Muscle tissue, much like other tissues in the body, has regenerative properties. Specific stem cells (myoblasts) are activated in the muscle in response to injury and certain exercises.  The process of stimulating these stem cells to form into new muscle fibers (myotubes) is called myogenesis, and it occurs through a series of epigenetically regulated events. Determining whether epigenetic modifications effect myogenesis intrigued the Lund researchers.

Epigenetic factors are critical during development and help regulate cell-type specificity, chromatin stability, and gene expression. Environmental influences like exercise, diet, age, and diseases can alter epigenetic mechanisms like DNA methylation in muscle tissue as well as other tissues. In a prior study, the team discovered irregular epigenetic and transcriptional changes during myoblast differentiation in individuals with obesity, a major risk factor for T2D.

For this study, the team investigated genome-wide expression and DNA methylation in the primary myoblasts and myotubes of people with and without T2D. The participants were matched by age, gender, and body mass index, and all cell handling conditions were kept equivalent. The results revealed 42 unique genes that were differentially expressed in the myotubes (fibers), while 20 of these genes, including the VPS30, were identified as being differentially expressed in the myoblasts (stem cells) as well. The researchers also analyzed mature muscle cells, and they compared epigenetic patterns before vs. after cell differentiation in the two groups. 

According to lead author and professor of epigenetics at Lund University, Charlotte Ling, the team found more than double the epigenetic modifications in the T2B group during the differentiation from stem cell to mature cell. She stated, “Muscle-specific genes were not regulated normally, and epigenetics did not function in the same way in cells from people with type 2 diabetes.”

“The study clearly showed that muscle stem cells that lack the function of the gene VPS39, which is lower in type-2 diabetes, also lack the ability to form new mature muscle cells.” said Johanna Säll Sernevi, Lund University postdoc researcher and author. She explained that the stem cells lacking VPS39 had disrupted epigenetic machinery that won’t allow them to change their metabolism; therefore, the cells breakdown and die.

The researchers confirmed their findings with a further study using a mouse model for VPS39-deficiency. Just like the individuals with T2D, the mice had distorted gene expression and lowered glucose absorption in the muscle tissue.

This study is the first ever to link VPS39 to muscle loss in T2D. Knowing how important this gene is to muscle cell sugar absorbance makes it an ideal, potential therapeutic target for diabetes. Still, determining exactly how this malfunction can be corrected requires more research. 

“The genome, our DNA, cannot be changed, although epigenetics in effect does. With this new knowledge, it is possible to change the dysfunctional epigenetics that occur in type 2 diabetes. For example, by regulating proteins, stimulating or increasing the amount of the VPS39 gene, it would be possible to affect the muscles’ ability to regenerate and absorb sugar,” concludes Ling.

Source: Cajsa Davegårdh, et al. (2021). VPS39-deficiency observed in type 2 diabetes impairs muscle stem cell differentiation via altered autophagy and epigeneticsNature Communications.

Reference: Muscle gene linked to type 2 diabetes. Lund University, April 23, 2021.

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