P27 dihydroxylation of Lrpprc declines ~20% in muscle wasting from cancer, dexamethasone, and aging, and mimicking this reduction decreases muscle force by 23-39%.
A decline in P27 dihydroxylation of Lrpprc is a shared marker of skeletal muscle wasting across diverse catabolic stimuli and contributes to muscle weakness.
ABSTRACT Background Skeletal muscle wasting and weakness are prominent disease features. Originally considered to arise from common transcriptional changes, recent analyses demonstrated that different stimuli induce muscle wasting via largely distinct mRNA and protein changes. Methods Here, we examined the post‐translational modifications (PTMs) associated with muscle wasting induced by cancer ( n = 15 078), dexamethasone ( n = 15 078) and aging ( n = 8777) in mice by utilising the JUMPptm pipeline to recover modified peptides from TMT (tandem mass tag) mass spectrometry analyses. Results We find that most PTMs that are significantly regulated are stimulus‐specific and that only a few are cross‐shared ( n = 10; p 0.05) on muscle force in young and old mice. Mechanistically, Lrpprc P27A does not affect proteostasis and mitochondrial function compared to control Lrpprc WT but impairs (> 60% decline; p < 0.05) the expression of genes necessary for muscle strength, including the apelin receptor Aplnr and Col6a2/6 collagens. Moreover, Lrpprc P27A reduces type 2b myofibre size (13% decline; p < 0.01) in old but not in young age. Conclusions These analyses identify atrophy‐associated PTMs that provide refined biomarkers for fingerprinting the atrophic stimulus. Although most PTMs are stimulus‐specific, P27 dihydroxylation of Lrpprc declines during muscle wasting induced by cancer, dexamethasone and aging, suggesting that this is a general atrophy marker. Experimental up‐regulation of the atrophy‐mimicking variant Lrpprc P27A reduces muscle force compared to wild‐type Lrpprc in young and old mice, suggesting that atrophy‐associated P27 dihydroxylation contributes to disease‐associated muscle weakness.
Stephan et al. (2026) studied this question. P27 dihydroxylation of Lrpprc declines ~20% in muscle wasting from cancer, dexamethasone, and aging, and mimicking this reduction decreases muscle force by 23-39%.