Carboxyl-terminal modulator protein (CTMP) deficiency mitigates denervation-induced skeletal muscle atrophy

• Published in: Biochemical and biophysical research communications Vol. 644; pp. 155 - 161
• Main Authors: Wang, Junmei, Tierney, Lydia, Wilson, Christopher, Phillips, Victoria, Goldman, Lillian, Mumaw, Christen, Muang, En, Walker, Chandler L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 12.02.2023
• Subjects: Akt signaling; Animals; Carrier Proteins - metabolism; CTMP; Denervation; Mice; Muscle atrophy; Muscle, Skeletal - metabolism; Muscular Atrophy - metabolism; Nerve injury; Palmitoyl-CoA Hydrolase - metabolism; Proto-Oncogene Proteins c-akt - metabolism; FOXO; Muscle atrophy; CTMP-KO; Nerve injury; ALS; Akt signaling; NMJ; CTMP; GSK3β; mTOR; 4E-BP1; MuRF-1; Denervation
• ISSN: 0006-291X; 1090-2104
• DOI: 10.1016/j.bbrc.2023.01.023

Denervated skeletal muscles show decreased Akt activity and phosphorylation, resulting in atrophy. Akt inhibits downstream transcription of atrophy-associated ubiquitin ligases like muscle ring-finger protein 1 (MuRF-1). In addition, reduced Akt signaling contributes to aberrant protein synthesis in muscles. In ALS mice, we recently found that carboxyl-terminator modulator protein (CTMP) expression is increased and correlated with reduced Akt signaling in atrophic skeletal muscle. CTMP has also been implicated in promoting muscle degeneration and catabolism in an in vitro muscle atrophy model. The present study examined whether sciatic nerve injury (SNI) stimulated CTMP expression in denervated skeletal muscle during muscle atrophy. We hypothesized that CTMP deficiency would reduce neurogenic atrophy and reverse Akt signaling downregulation. Compared to the unaffected contralateral muscle, wild-type (WT) gastrocnemius muscle had a significant increase in CTMP (p < 0.05). Furthermore, denervated CTMP knockout (CTMP-KO) gastrocnemius weighed more than WT muscle (p < 0.05). Denervated CTMP-KO gastrocnemius also showed higher Akt and downstream glycogen synthase kinase 3β (GSK3β) phosphorylation compared to WT muscle (p < 0.05) as well as ribosomal proteins S6 and 4E-BP1 phosphorylation (p < 0.001 and p < 0.05, respectively). Moreover, CTMP-KO mice showed significantly lower levels of E3 ubiquitin ligase MuRF-1 and myostatin than WT muscle (p < 0.05). Our findings suggest that CTMP is essential to muscle atrophy after denervation and it may act by reducing Akt signaling, protein synthesis, and increasing myocellular catabolism. [Display omitted] •Muscle atrophy accompanies a broad variety of diseases and disorders.•The shift from muscle maintenance to atrophy centers on downregulated Akt kinase and downstream signaling.•CTMP antagonizes Akt activity and is upregulated in atrophic muscle in neuromuscular and inflammatory conditions.•This study aimed to confirm a role for CTMP as a key protein in promoting muscle atrophy following nerve injury.