Integrated genomic and proteomic analyses identify stimulus-dependent molecular changes associated with distinct modes of skeletal muscle atrophy

• Published in: Cell reports (Cambridge) Vol. 37; no. 6; p. 109971
• Main Authors: Hunt, Liam C., Graca, Flavia A., Pagala, Vishwajeeth, Wang, Yong-Dong, Li, Yuxin, Yuan, Zuo-Fei, Fan, Yiping, Labelle, Myriam, Peng, Junmin, Demontis, Fabio
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 09.11.2021
• Subjects: Aging; Animals; atroprotein; cancer-induced cachexia; CCN1/Cyr61; dexamethasone; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; muscle atrophy; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Atrophy - genetics; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; myofiber atrophy; myokine; Proteome; proteomics; sarcopenia; Sarcopenia - genetics; Sarcopenia - metabolism; Sarcopenia - pathology; Transcriptome; myofiber atrophy; dexamethasone; CCN1/Cyr61; proteomics; cancer-induced cachexia; myokine; muscle atrophy; aging; atroprotein; sarcopenia
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2021.109971

Skeletal muscle atrophy is a debilitating condition that occurs with aging and disease, but the underlying mechanisms are incompletely understood. Previous work determined that common transcriptional changes occur in muscle during atrophy induced by different stimuli. However, whether this holds true at the proteome level remains largely unexplored. Here, we find that, contrary to this earlier model, distinct atrophic stimuli (corticosteroids, cancer cachexia, and aging) induce largely different mRNA and protein changes during muscle atrophy in mice. Moreover, there is widespread transcriptome-proteome disconnect. Consequently, atrophy markers (atrogenes) identified in earlier microarray-based studies do not emerge from proteomics as generally induced by atrophy. Rather, we identify proteins that are distinctly modulated by different types of atrophy (herein defined as “atroproteins”) such as the myokine CCN1/Cyr61, which regulates myofiber type switching during sarcopenia. Altogether, these integrated analyses indicate that different catabolic stimuli induce muscle atrophy via largely distinct mechanisms. [Display omitted] •Deep-coverage proteomics reveal molecular changes responsible for muscle wasting•Different catabolic stimuli induce muscle atrophy via largely distinct mechanisms•Transcriptome-proteome disconnect occurs during muscle wasting•Atroproteins are proteins modulated by atrophic stimuli Skeletal muscle wasting is caused by many catabolic stimuli, which were thought to act via shared mechanisms. Hunt et al. now show that distinct catabolic stimuli induce muscle wasting via largely different molecular changes. The authors identify atrophy-associated proteins (“atroproteins”) that may represent diagnostic biomarkers and/or therapeutic targets.