A. Elisabeth Gressler

Skeletal muscle atrophy is a pathological condition characterized by the loss of muscle mass and strength, driven by diverse stimuli including disuse, malnutrition, acute and chronic inflammation, ...

Skeletal muscle atrophy is a pathological condition characterized by the progressive loss of muscle mass and function, driven by factors such as disuse, inflammation, and aging. While the ubiquitin-proteasome system is established as the central mediator of myofibrillar protein degradation, the role of autophagy in selective protein turnover remains largely unexplored. To address this, we employed a quantitative, time-resolved analysis of protein synthesis and degradation in C2C12 myotubes undergoing TNF-α-induced atrophy, using dynamic Stable Isotope Labeling by Amino Acids in Cell Culture (dynamic SILAC) coupled with LC-MS/MS. Our data challenges the classical view of atrophy as a uniform, degradation-centric process. Instead, we reveal temporally distinct patterns of selective protein turnover, including differential degradation of myofibrillar, ribosomal, and endoplasmic reticulum (ER)-resident proteins. Early atrophy is characterized by suppressed short-term protein synthesis, increased ubiquitin-ligase expression, proteasomal activation, and ribosome turnover. In contrast, late atrophy features proteasome-dependent myofibrillar protein degradation, selective synthesis of mitochondrial ribosomes and cytoplasmic ribosome degradation, indicative of metabolic adaptation. Moreover, we identify a temporal shift in autophagic selectivity: from ER homeostasis maintenance to a stress-induced ER-degradation program. Notably, inhibition of autophagy during atrophy leads to accumulation of ER-phagy receptors Tex264 and Calcoco1, implicating ER-phagy as a key contributor to atrophic remodeling, underscoring an underexplored regulatory mechanism in muscle proteostasis. By elucidating the role of autophagy in degradation of the ER, this study opens new avenues for therapeutic interventions targeting proteostasis regulation in inflammation-induced muscle-wasting disorders, ultimately contributing to a more refined understanding of muscle atrophy beyond proteasomal degradation.

The ability of the fungal pathogen Candida albicans to undergo a yeast-to-hypha transition is believed to be a key virulence factor, as filaments mediate tissue damage. Here, we show that virulence is not necessarily reduced in filament-deficient strains, and the results depend on the infection model used. We generate a filament-deficient strain by deletion or repression of EED1 (known to be required for maintenance of hyphal growth). Consistent with previous studies, the strain is attenuated in damaging epithelial cells and macrophages in vitro and in a mouse model of intraperitoneal infection. However, in a mouse model of systemic infection, the strain is as virulent as the wild type when mice are challenged with intermediate infectious doses, and even more virulent when using low infectious doses. Retained virulence is associated with rapid yeast proliferation, likely the result of metabolic adaptation and improved fitness, leading to high organ fungal loads. Analyses of cytokine responses in vitro and in vivo, as well as systemic infections in immunosuppressed mice, suggest that differences in immunopathology contribute to some extent to retained virulence of the filament-deficient mutant. Our findings challenge the long-standing hypothesis that hyphae are essential for pathogenesis of systemic candidiasis by C. albicans.