Eraslan, S. | Search bioRxiv

bioRxiv2026

The interferon-gamma response pathway is a targetable driver of FSHD muscular dystrophy progression

Facioscapulohumeral muscular dystrophy (FSHD) is a leading neuromuscular disorder caused by the aberrant expression of the transcription factor double homeobox 4 (DUX4) in skeletal muscle. While DUX4 is normally restricted to early embryonic development, its reactivation in FSHD triggers chronic inflammation and progressive muscle degeneration. However, the precise molecular links between DUX4 and persistent immune activation remain poorly understood. Here, we show that DUX4 induces a viral mimicry-like pathway that is fundamentally uncoupled from canonical type I interferon (IFN) activation. Instead, DUX4 establishes a non-canonical innate immune state dominated by IFN-gamma signaling, providing a mechanistic explanation for the non-resolving inflammation characteristic of the disease. We demonstrate that while IFN-gamma treatment alone is sufficient to recapitulate key DUX4 pathogenic effects, its inhibition rescues muscle inflammation and halts disease progression in FSHD models. These findings define a skewed viral mimicry process driven by a disease-specific transcription factor and identify IFN-gamma as a primary therapeutic target for tissue-informed immunomodulation in muscular dystrophy.

genetics↗

bioRxiv2018

Saccharomyces cerevisiae adapted to grow in the presence of low-dose rapamycin exhibit altered amino acid metabolism

Rapamycin is a potent inhibitor of the highly conserved TOR kinase, the nutrient-sensitive controller of growth and aging. It has been utilised as a chemotherapeutic agent due to its anti-proliferative properties and as an immunosuppressive drug, and is also known to extend lifespan in a range of eukaryotes from yeast to mammals. However, the mechanisms through which eukaryotic cells adapt to sustained exposure to rapamycin have not yet been thoroughly investigated. Here, S. cerevisiae response to long-term rapamycin exposure was investigated by identifying the physiological, transcriptomic and metabolic differences observed for yeast populations inoculated into low-dose rapamycin-containing environment. The effect of oxygen availability and acidity of extracellular environment on this response was further deliberated by controlling or monitoring the dissolved oxygen level and pH of the culture. Yeast populations grown in the presence of rapamycin reached higher cell densities complemented by an increase in their chronological lifespan, and these physiological adaptations were associated with a rewiring of the amino acid metabolism, particularly that of arginine. The ability to synthesise amino acids emerges as the key factor leading to the major mechanistic differences between mammalian and microbial TOR signalling pathways in relation to nutrient recognition. Furthermore, oxygen levels and extracellular acidity of the culture were observed to conjointly affect yeast populations, virtually acting as coupled physiological effectors; cells were best adapted when maximal oxygenation of the culture was maintained in slightly acidic pH, any deviation necessitated more extensive readjustment to additional stress factors.

biochemistry↗