Control of skeletal muscle atrophy in response to disuse: clinical/preclinical contentions and fallacies of evidence

Atherton, Philip J.; Greenhaff, Paul L.; Phillips, Stuart M.; Bodine, Sue C.; Adams, Christopher M.; Lang, Charles H.

doi:10.1152/ajpendo.00257.2016

Cited by 131 publications

(126 citation statements)

References 44 publications

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“…Excessive protein degradation is the main cause for skeletal muscle atrophy, which is harmful to human health and leads to muscle fatigue and reduced life span (28)(29)(30)(31). Abnormal protein degradation and muscle atrophy generally occur with genetic mutation (DMD) (32), hormone exposure (glucocorticoid) (33), or disease (cachexia) (34).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2017

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“…Therefore, it was somewhat unexpected that muscle proteasomal activity was found to be increased during sepsis-recovery. However, accumulating evidence now suggests that it is often erroneous to equate changes in atrogin-1 and MuRF1 with coordinated changes in proteasomal activity and protein degradation (30). In a previously published model, where rats received a single intravenous injection of live E. coli , proteasomal activity was increased at 6 days post-infection but UPP activity had returned to basal levels by day 10 (31).…”

Section: Discussionmentioning

confidence: 99%

Restorative Mechanisms Regulating Protein Balance in Skeletal Muscle During Recovery From Sepsis

Crowell

Soybel

Lang

2017

Shock

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Muscle deconditioning is commonly observed in patients surviving sepsis. Little is known regarding the molecular mechanisms regulating muscle protein homeostasis during the recovery or convalescence phase. We adapted a sepsis-recovery mouse model that uses cecal ligation and puncture (CLP), followed 24 h later by cecal resection and antibiotic treatment, to identify putative cellular pathways regulating protein synthesis and breakdown in skeletal muscle. Ten days after CLP, body weight and food consumption did not differ between control and sepsis-recovery mice, butgastrocnemius weight was reduced. During sepsis-recovery, muscle protein synthesis was increased 2-fold and associated with enhanced mTOR kinase activity (4E-BP1 and S6K1 phosphorylation). The sepsis-induced increase in 4E-BP1 was associated with enhanced formation of the eIF4E-eIF4G active cap-dependent complex, while the increased S6K1 was associated with increased phosphorylation of downstream targets S6 and eIF4B. Proximal to mTOR, sepsis-recovery increased Akt and TSC2 phosphorylation, did not alter AMPK phosphorylation, and decreased REDD1 protein content. Despite the decreased mRNA content for the E3 ubiquitin ligases atrogin-1 and MuRF1, proteasomal activity was increased 50%. In contrast, sepsis-recovery was associated with an apparent decrease in autophagy (e.g., increased ULK-1 phosphorylation, decreased LCB3-II and increased p62). The mRNA content for IL-1β, IL-18, TNFα and IL-6 in muscle was elevated in sepsis-recovery. During recovery after sepsis skeletal muscle responds with an increase in Akt-TSC2-mTOR-dependent protein synthesis and decreased autophagy, but full restoration of muscle protein content may be slowed by the continued stimulation of ubiquitin-proteasome activity.

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“…Given that muscle anabolism and catabolism are coupled to physical activity[63], mechanical unloading after RCT likely causes myofiber atrophy by shifting muscle metabolism from anabolic to catabolic processes. The initial hypothesis of the present study is that MP infiltration exacerbates SS atrophy.…”

Section: Discussionmentioning

confidence: 99%

Quantitative Analysis of Immune Cell Subset Infiltration of Supraspinatus Muscle After Severe Rotator Cuff Injury

Krieger

Tellier

Ollukaren

et al. 2017

Regen. Eng. Transl. Med.

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Rotator cuff tears cause muscle degeneration that is characterized by myofiber atrophy, fatty infiltration, and fibrosis and is minimally responsive to current treatment options. The underlying pathogenesis of rotator cuff muscle degeneration remains to be elucidated, and increasing evidence implicates immune cell infiltration as a significant factor. Because immune cells are comprised of highly heterogeneous subpopulations that exert divergent effects on injured tissue, understanding trafficking and accumulation of immune subpopulations may hold the key to more effective therapies. The present study quantifies subpopulations of immune cells infiltrating the murine supraspinatus muscle after severe rotator cuff injury that includes tenotomy and denervation. Rotator cuff injury stimulates dramatic infiltration of mononuclear phagocytes, enriches mononuclear phagocytes in non-classical subpopulations, and enriches T lymphocytes in TH and Treg subpopulations. The combination of tenotomy plus denervation significantly increases mononuclear phagocyte infiltration, enriches macrophages in the non-classical subpopulation, and decreases T lymphocyte enrichment in TH cells compared to tenotomy alone. Depletion of circulating monocytes via liposomal clodronate accelerates supraspinatus atrophy after tenotomy and denervation. The study may aid rational design of immunologically smart therapies that harness immune cells to enhance outcomes after rotator cuff tears.

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Control of skeletal muscle atrophy in response to disuse: clinical/preclinical contentions and fallacies of evidence

Abstract: Atherton PJ, Greenhaff PL, Phillips SM, Bodine SC, Adams CM, Lang CH. Control of skeletal muscle atrophy in response to disuse: clinical/preclinical contentions and fallacies of evidence*.

Cited by 131 publications

References 44 publications

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

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

Restorative Mechanisms Regulating Protein Balance in Skeletal Muscle During Recovery From Sepsis

Quantitative Analysis of Immune Cell Subset Infiltration of Supraspinatus Muscle After Severe Rotator Cuff Injury

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