Search

Activating transcription factor 4 (ATF4) is involved in muscle atrophy through the overexpression of some atrogenes. However, it also controls the transcription of genes involved in muscle homeostasis maintenance. Here, we explored the effect of ATF4 activation by the pharmacological molecule halofuginone during hindlimb suspension (HS)-induced muscle atrophy. Firstly, we reported that periodic activation of ATF4-regulated atrogenes (Gadd45a, Cdkn1a, and Eif4ebp1) by halofuginone was not associated with muscle atrophy in healthy mice. Secondly, halofuginone-treated mice even showed reduced atrophy during HS, although the induction of the ATF4 pathway was identical to that in untreated HS mice. We further showed that halofuginone inhibited transforming growth factor-β (TGF-β) signalling, while promoting bone morphogenetic protein (BMP) signalling in healthy mice and slightly preserved protein synthesis during HS. Finally, ATF4-regulated atrogenes were also induced in the atrophy-resistant muscles of hibernating brown bears, in which we previously also reported concurrent TGF-β inhibition and BMP activation. Overall, we show that ATF4-induced atrogenes can be uncoupled from muscle atrophy. In addition, our data also indicate that halofuginone can control the TGF-β/BMP balance towards muscle mass maintenance. Whether halofuginone-induced BMP signalling can counteract the effect of ATF4-induced atrogenes needs to be further investigated and may open a new avenue to fight muscle atrophy. Finally, our study opens the way for further studies to identify well-tolerated chemical compounds in humans that are able to fine-tune the TGF-β/BMP balance and could be used to preserve muscle mass during catabolic situations.

Epub ahead of print; PURPOSE: To compare the effects of 8-week eccentric (ECC) versus concentric (CON) training using downhill and uphill running in rats on whole body composition, bone mineral density (BMD), and energy expenditure (EE). METHODS: Animals were randomly assigned to one of the following groups: 1) control (CTRL), 2) +15% uphill-running slope (CON), 3) -15% downhill-running slope (ECC15) and 4) -30% downhill-running slope (ECC30). Those programs enabled to achieve conditions of iso-power output for CON and ECC15 and of iso-oxygen uptake (VO2) for CON and ECC30. Trained rats ran 45min at 15 mmin five times per week. Total (TBM), fat (FBM) and lean (LBM) body mass measured through EchoMRI, and 24-hour EE including basal metabolic rate (BMR) assessed using PhenoMaster/LabMaster cage system were obtained before and after training. At sacrifice, the right femur was collected for bone parameters analysis. RESULTS: While TBM increased in all groups over the 8-week period, almost no change occurred for FBM in exercised groups (CON: -4.8+/-6.18 g; ECC15: 0.6+/-3.32 g; ECC30: 2.6+/-6.01 g). The gain in LBM was mainly seen for ECC15 (88.9+/-6.85 g) and ECC30 (101.6+/-11.07 g). ECC was also seen to positively affect BMD. An increase in BMR from baseline was seen in exercise groups (CON: 13.9+/-4.13 kJ.day; ECC15: 11.6+/-5.10 kJ.day; ECC30: 18.3+/-4.33 kJ.day) but not in CTRL one. This difference disappeared when BMR was normalized for LBM. CONCLUSIONS: Results indicate that for iso-VO2 training, the impact on LBM and BMD is enhanced with ECC as compared to CON, and that for iso-power but lower VO2 ECC, an important stimulus for adaptation is still observed. This provides further insights for the use of ECC in populations with cardiorespiratory exercise limitations.