摘要：We previously reported that growth promoter-induced skeletal muscle hypertrophy co-ordinately upregulated expression of genes associated with an integrated stress response (ISR), as well as potential ISR regulators. We therefore used Adeno-Associated Virus (AAV)-mediated overexpression of these genes, individually or in combination, in mouse skeletal muscle to test whether they induced muscle hypertrophy. AAV of each target gene was injected into mouse
Tibialis anterior (TA) and effects on skeletal muscle growth determined 28 days later. Individually, AAV constructs for Arginase-2 (
Arg2) and Activating transcription factor-5 (
Atf5) reduced hindlimb muscle weights and upregulated expression of genes associated with an ISR. AAV-
Atf5 also decreased Myosin heavy chain (MyHC)-IIB mRNA, but increased MyHC-IIA and isocitrate dehydrogenase-2 (
Idh2) mRNA, suggesting ATF5 is a novel transcriptional regulator of
Idh2. AAV-
Atf5 reduced the size of both TA oxidative and glycolytic fibres, without affecting fibre-type proportions, whereas
Atf5 combined with
Cebpg (CCAAT enhancer binding protein-gamma) only reduced the size of glycolytic fibres and tended to increase the proportion of oxidative fibres. It is likely that persistent
Atf5 overexpression maintains activation of the ISR, thereby reducing protein synthesis and/or increasing protein degradation and possibly apoptosis, resulting in inhibition of muscle growth, with overexpression of
Arg2 having a similar effect.
