Most post-translational modifications associated with muscle wasting are stimulus-specific, but P27 dihydroxylation of Lrpprc declines during muscle wasting induced by cancer, dexamethasone, and aging, and experimental expression of the dihydroxylation-resistant variant LrpprcP27A reduces muscle force in young and old mice, suggesting this modification contributes to disease-associated muscle weakness.
Key Findings
Results
Most significantly regulated PTMs associated with muscle wasting are stimulus-specific, with only a small number shared across atrophic conditions.
PTMs were examined in cancer (n=15,078), dexamethasone (n=15,078), and aging (n=8,777) conditions in mice using the JUMPptm pipeline with TMT mass spectrometry.
Only 10 PTMs were cross-shared across conditions (p<0.05).
The majority of significantly regulated PTMs were specific to their respective atrophic stimulus.
Results
P27 dihydroxylation of Lrpprc declines with muscle wasting regardless of the atrophic trigger.
Lrpprc (leucine-rich pentatricopeptide repeat containing) is an RNA binding protein and transcriptional co-activator mutated in Leigh syndrome, a mitochondrial disease.
P27 dihydroxylation of Lrpprc decreased approximately 20% (p<0.05) across all three atrophic stimuli: cancer, dexamethasone, and aging.
This modification was one of only 10 PTMs identified as cross-shared (p<0.05) among the atrophy conditions.
Results
Electroporation of the dihydroxylation-resistant LrpprcP27A variant reduces muscle force in both young and old male mice compared to contralateral LrpprcWT electroporation.
In young male mice, LrpprcP27A reduced muscle force by approximately 23%–39% compared to contralateral LrpprcWT electroporation (p<0.01).
In old male mice, LrpprcP27A reduced muscle force by approximately 26%–36% compared to contralateral LrpprcWT electroporation (p<0.01).
Comparison of LrpprcWT versus GFP electroporation showed mostly non-significant effects (p>0.05) on muscle force in both young and old mice.
These results indicate that a decline in Lrpprc P27 dihydroxylation contributes to muscle weakness in response to diverse catabolic stimuli.
Results
LrpprcP27A impairs expression of genes necessary for muscle strength, including the apelin receptor Aplnr and Col6a2/6 collagens.
LrpprcP27A caused a greater than 60% decline (p<0.05) in expression of genes necessary for muscle strength.
Affected genes include the apelin receptor Aplnr and Col6a2/6 collagens.
LrpprcP27A did not affect proteostasis or mitochondrial function compared to control LrpprcWT.
Results
LrpprcP27A reduces type 2b myofibre size in old but not young mice.
LrpprcP27A caused a 13% decline in type 2b myofibre size (p<0.01) in old mice.
This effect on myofibre size was not observed in young mice.
The age-specific effect on fibre size was specific to type 2b myofibres.
Results
Atrophy-associated PTMs can serve as refined biomarkers for fingerprinting the specific atrophic stimulus.
Because the vast majority of PTMs are stimulus-specific, they differentiate between muscle wasting caused by cancer, dexamethasone, and aging.
The stimulus-specificity of most PTMs contrasts with the cross-shared decline in Lrpprc P27 dihydroxylation.
The analyses were based on examining modified peptides recovered from TMT mass spectrometry analyses using the JUMPptm pipeline.
Stephan A, Graca F, Poudel S, Fu Y, Wang Y, Labelle M, et al.. (2026). Largely Distinct Post-Translational Modifications Differentiate Skeletal Muscle Wasting Caused by Cancer, Dexamethasone and Aging.. Journal of cachexia, sarcopenia and muscle. https://doi.org/10.1002/jcsm.70220