α‐Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway

Abstract

Skeletal muscle atrophy due to excessive protein degradation is the main cause for muscle dysfunction, fatigue, and weakening of athletic ability. Endurance exercise is effective to attenuate muscle atrophy, but the underlying mechanism has not been fully investigated. α-Ketoglutarate (AKG) is a key intermediate of tricarboxylic acid cycle, which is generated during endurance exercise. Here, we demonstrated that AKG effectively attenuated corticosterone-induced protein degradation and rescued the muscle atrophy and dysfunction in a Duchenne muscular dystrophy mouse model. Interestingly, AKG also inhibited the expression of proline hydroxylase 3 (PHD3), one of the important oxidoreductases expressed under hypoxic conditions. Subsequently, we identified the β adrenergic receptor (ADRB2) as a downstream target for PHD3. We found AKG inhibited PHD3/ADRB2 interaction and therefore increased the stability of ADRB2. In addition, combining pharmacologic and genetic approaches, we showed that AKG rescues skeletal muscle atrophy and protein degradation through a PHD3/ADRB2 mediated mechanism. Taken together, these data reveal a mechanism for inhibitory effects of AKG on muscle atrophy and protein degradation. These findings not only provide a molecular basis for the potential use of exercise-generated metabolite AKG in muscle atrophy treatment, but also identify PHD3 as a potential target for the development of therapies for muscle wasting.-Cai, X., Yuan, Y., Liao, Z., Xing, K., Zhu, C., Xu, Y., Yu, L., Wang, L., Wang, S., Zhu, X., Gao, P., Zhang, Y., Jiang, Q., Xu, P., Shu, G. α-Ketoglutarate prevents skeletal muscle protein degradation and muscle atrophy through PHD3/ADRB2 pathway.

α-ketoglutaric acid stimulates muscle hypertrophy and fat loss through OXGR1-dependent adrenal activation

“…EV2D and EV2J). This is consistent with our previous observations that AKG promotes skeletal muscle hypertrophy and protein synthesis (Cai et al, 2016) while inhibits skeletal muscle protein degradation and muscle atrophy (Cai et al, 2018).…”

“…Additionally, AKG also decreased the basal respiration of C2C12 cells (Fig. EV5E-F), suggesting an autocrine regulatory role of AKG in muscle metabolism, which is consistent with our previous findings (Cai et al, 2018; Cai et al, 2016). Importantly, AKG dramatically decreased basal respiration and enhanced spare respiratory capacity (SRC) of adrenal chromaffin cells (Fig.…”

“…When fed on chow, AKG-treated mice showed upregulation of lean muscle mass and body weight gain. These results are consistent with our previous observations that AKG increases muscle protein synthesis (Cai et al, 2016) while decreasing muscle protein degradation (Cai et al, 2018). On the other hand, we found AKG treatment increases BAT thermogenesis and decrease fat mass, which is consistent with the previous report that AKG increases BAT adipogenesis and thermogenesis via an epigenetic way (Yang et al, 2016).…”

“…So OXGR1 protects HFD-induced muscle loss when circulating AKG is low, which is independent of resistance exercise. The protective effect of OXGR1 is possibly mediated by directly increasing muscle protein synthesis (Cai et al, 2016) and decreasing muscle protein degradation (Cai et al, 2018). Of course, it is also possible that other indirect pathways are involved.…”

“…Cellular OCR was determined using an Agilent Seahorse XFp analyzer (S7802A, Agilent technologies). The culture of C2C12 and HepG2 cell were described as previously (Cai et al, 2018; Xu et al, 2018). C2C12 (China Infrastructure of Cell Line Researcher, China) and primary brown adipocytes were plated and differentiated in Seahorse XFp cell culture miniplates (103022100, Agilent technologies).…”