Ligands for FKBP12 Increase Ca2+ Influx and Protein Synthesis to Improve Skeletal Muscle Function

Abstract

Background:Rapamycin is a known inhibitor of protein synthesis but also modulates the activity of RyR1. Results: FKBP12 deficiency and low doses of either rapamycin or SLF increase, rather than decrease, protein synthesis and improve muscle function. Conclusion: In skeletal muscle, FKBP12 regulates Ca 2ϩ influx, Ca 2ϩ store refilling, and protein synthesis. Significance: This study lays the groundwork for the development of interventions to slow muscle fatigue.

Targeting deregulated AMPK/mTORC1 pathways improves muscle function in myotonic dystrophy type I

“…Notably, vacuoles remained present in muscle fibers from 12-month-old AICAR-or rapamycin-treated HSA LR mice ( Figure 8A), indicating that the treatments were not sufficient to reverse muscle alterations related to impaired autophagy in aging mice. As no myotonia was detected in the slow, soleus muscle of HSA LR mice and as AICAR and rapamycin were previously shown to alter muscle fiber types (42,43), we tested whether changes in muscle function upon treatments were related to modification of muscle metabolic and contractile capacities. By reduced nicotinamide adenine dinucleotide (NADH) staining, we first observed that the overall oxidative property of TA muscle was unchanged in AICARand rapamycin-treated mutant mice, compared with untreated animals ( Figure 8B).…”

A chemical chaperone improves muscle function in mice with a RyR1 mutation

“…For assessment of newly synthesized proteins we used in vivo puromycin labelling4662. Briefly, mice (14–15 weeks of age) were deprived of food for 6 h and refed for 2 h. Propofol (18 μl g −1 ) was intraperitoneally injected in mice after 70 min of refeeding.…”

217th ENMC International Workshop: RYR1-related myopathies, Naarden, The Netherlands, 29–31 January 2016

“…Dr Hamilton described the use of two mouse models of RYR1-RMs (Y522S and I4898T) to assess mechanisms of disease and develop new interventions. In particular, she discussed the efficacy of AICAR [40], N-acetylcysteine [41], and low dose rapamycin [42] for improving muscle function in these mouse models. She also discussed recent findings with the I4898T mice (a RyR1 pore blocking mutation) and the need for very different approaches to improving muscle function in these mice than those used with the Y522S mice with Ca 2+ leaky mutations.…”