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Abstract Calorie restriction (CR) and treatment with rapamycin (RM), an inhibitor of the mTORC1 growth-promoting signaling pathway, are known to slow aging and promote health from worms to humans. At the transcriptome and proteome levels, long-term CR and RM treatments have partially overlapping effects, while their impact on protein phosphorylation within cellular signaling pathways have not been compared. Here we measured the phosphoproteomes of soleus, tibialis anterior, triceps brachii and gastrocnemius muscles from adult (10 months) and 30-month-old (aged) mice receiving either a control, a calorie restricted or an RM containing diet from 15 months of age. We reproducibly detected and extensively analyzed a total of 6960 phosphosites, 1415 of which are not represented in standard repositories. We reveal the effect of these interventions on known mTORC1 pathway substrates, with CR displaying greater between-muscle variation than RM. Overall, CR and RM have largely consistent, but quantitatively distinct long-term effects on the phosphoproteome, mitigating age-related changes to different degrees. Our data expands the catalog of protein phosphorylation sites in the mouse, providing important information regarding their tissue-specificity, and revealing the impact of long-term nutrient-sensing pathway inhibition on mouse skeletal muscle.

Exploring the relationship between mTORC1 and the ubiquitin-proteasome system, light is shed on the paradox between mTORC1-mediated muscle hypertrophy induced by PKB/Akt and the muscle atrophy induced by mTORC1 alone.

Anastasiya Börsch, Daniel Ham, and colleagues generated a time series of phenotypic measurements and RNA-Seq data from mouse skeletal muscle and comparatively analyzed these along comparable rat and human data, to assess the relevance of rodent models for human muscle aging. This study draws attention to the utility of phenotypic measurements in analyzing aging-related molecular data, as several measurements such as muscle mass, were better indicators of muscle health than chronological age.