Immune pathway may contribute to muscle damage in myotonic dystrophy
Cell study links type I interferon signaling to stress and mitochondrial problems
Written by |
An immune signaling pathway involving type I interferon (IFN-I) may be a potential therapeutic target for muscle damage in people with myotonic dystrophy type 1 (DM1), a new study suggests.
An examination of immature muscle cells from children with DM1 found that increased IFN-I signaling was associated with stress in the cell’s protein-processing machinery and mitochondrial dysfunction.
The study, “An Ultrastructural and Proteomic Analysis in DM1 Young Adults’ Myoblasts: Stressed RER and Mitochondrial Dysfunction Involvement,” was published in the Journal of Cellular and Molecular Medicine.
Expanded DMPK repeats disrupt normal muscle-cell function
In DM1, a segment of the DMPK gene is abnormally repeated, usually more than 50 times. This leads to the production of an extra-long messenger RNA (mRNA), the intermediary molecule that carries the genetic code to make proteins, which drives muscle dysfunction. Longer repeats are generally associated with earlier onset and more severe disease.
But how these abnormally long mRNAs drive progressive muscle loss and weakness remains unclear.
In previous work, a research team in Italy found that in the congenital form of DM1, the most severe type, the IFN-I immune pathway was abnormally activated in muscle cells and contributed to impaired myogenesis, the process by which precursor cells develop into mature muscle fibers.
In this new study, the team wanted to find out whether the same immune activation also occurred in muscle cells from older children with childhood-onset DM1.
Researchers collected immature muscle cells called myoblasts from muscle biopsies of two boys with childhood-onset DM1: an 8-year-old with about 800 repeats and a 13-year-old with around 1,300 repeats. Samples from two age-matched healthy boys served as controls. The myoblasts were grown in the lab and induced to develop into muscle fibers.
Under the microscope, DM1 myoblasts stretched into the spindle-shaped structures typical of maturing muscle cells, similar to those seen in control cells. By day three, they had formed muscle fibers, although fewer cells had developed well-structured fibers than in the control group.
When the team measured the activity of four genes linked to the IFN-I pathway (ISG15, OAS1, STAT1, and TLR4), all were significantly higher in both DM1 samples than in controls. Notably, ISG15 was already elevated at the start of maturation.
Despite this finding, the team noted that IFN-I signaling did not appear to directly reduce muscle-cell differentiation.
Cell stress and mitochondrial problems emerge in DM1 myoblasts
To investigate further, the researchers examined the rough endoplasmic reticulum (RER), a network of flattened, membrane-bound sacs inside a cell that produces and folds proteins. In control cells, the RER looked normal and well-organized.
In both patient samples, however, the RER appeared enlarged and lost its typical dense appearance, a condition called stressed RER (sRER). Two markers of this stress response, CHOP and ATF6, were significantly increased in both patient samples.
As the cells differentiated, further microscopy showed more abnormal mitochondria — the structures that produce most of the cell’s energy — in the DM1 cells than in controls.
The cells also showed a progressive increase in autophagic vacuoles, structures the cell uses to break down damaged components, with the boy carrying 1,300 repeats showing a significant increase. The researchers also observed damaged mitochondria inside these structures, consistent with the cells clearing damaged mitochondria.
At the molecular level, 122 proteins were present at higher levels in myoblasts from the boy with 1,300 repeats, while 140 were at lower levels than in controls. Functional analysis of these differences pointed to biological processes including muscle contraction, mitochondrial function, and endoplasmic reticulum stress.
“Our data suggest that this inappropriate activation of the IFN-I pathway contributes to muscle pathology, not by blocking differentiation directly, but through chronic stress signalling,” the researchers wrote.
These findings support a model in which “innate immune dysregulation plays a central role in DM1 muscle degeneration and highlight the IFN1 pathway as a potential therapeutic target for restoring normal muscle function.”
Leave a comment
Fill in the required fields to post. Your email address will not be published.