Abstract
Slow-twitch muscles, devoted to postural maintenance, experience atrophy and weakness during muscle disuse due to bed-rest, aging or spaceflight. These conditions impair motion activities and can have survival implications. Human and animal studies demonstrate the anabolic role of IGF-1 on skeletal muscle suggesting its interest as a muscle disuse countermeasure. Thus, we tested the role of IGF-1 overexpression on skeletal muscle alteration due to hindlimb unloading (HU) by using MLC/mIgf-1 transgenic mice expressing IGF-1 under the transcriptional control of MLC promoter, selectively activated in skeletal muscle. HU produced atrophy in soleus muscle, in terms of muscle weight and fiber cross-sectional area (CSA) reduction, and up-regulation of atrophy gene MuRF1. In parallel, the disuse-induced slow-to-fast fiber transition was confirmed by an increase of the fast-type of the Myosin Heavy Chain (MHC), a decrease of PGC-1α expression and an increase of histone deacetylase-5 (HDAC5). Consistently, functional parameters such as the resting chloride conductance (gCl) together with ClC-1 chloride channel expression were increased and the contractile parameters were modified in soleus muscle of HU mice. Surprisingly, IGF-1 overexpression in HU mice was unable to counteract the loss of muscle weight and the decrease of fiber CSA. However, the expression of MuRF1 was recovered, suggesting early effects on muscle atrophy. Although the expression of PGC-1α and MHC were not improved in IGF-1-HU mice, the expression of HDAC5 was recovered. Importantly, the HU-induced increase of gCl was fully contrasted in IGF-1 transgenic mice, as well as the changes in contractile parameters. These results indicate that, even if local expression does not seem to attenuate HU-induced atrophy and slow-to-fast phenotype transition, it exerts early molecular effects on gene expression which can counteract the HU-induced modification of electrical and contractile properties. MuRF1 and HDAC5 can be attractive therapeutic targets for pharmacological countermeasures and then deserve further investigations.
Highlights
The absence of gravitational loading, which occurs during physical inactivity due to prolonged bed rest, aging or spaceflight, predisposes humans to severe failure of vital tissues, such as cardiovascular system, bone and skeletal muscle
The results from this study add new insights into the mechanisms underlying the modifications in slow-twitch skeletal muscle due to inactivity and clarify the potential paracrine effect of IGF-1 overexpression in modulating these alterations
A few studies suggested that the mechanism of muscle wasting caused by disuse may involve a decreased IGF-1/PI3K signaling, with an increase of the expression of MuRF1 and atrogin-1 via modulation of the AKT/forkhead box O1 (FOXO) cascade [35,36]
Summary
The absence of gravitational loading, which occurs during physical inactivity due to prolonged bed rest, aging or spaceflight, predisposes humans to severe failure of vital tissues, such as cardiovascular system, bone and skeletal muscle. Similar skeletal muscle alterations are observed in the hindlimb unloaded (HU) rodent model. In rat and mouse soleus (Sol) muscle, HU produces severe atrophy and a slow-to-fast phenotype transition as shown by the modification of myosin heavy chain (MHC) isoform distribution. An increase of activity and expression of the ClC-1 muscle chloride channel, the channel responsible for the resting chloride conductance (gCl) is observed in HU animals toward the value typical of fast muscles. As already shown, this is important for muscle function, since gCl is pivotal for sarcolemma stability and for the fine tuning of the electrical and contractile properties. The modification of gCl in HU Sol muscle precedes the changes in MHC isoforms, suggesting that it may represent a key determinant of the phenotype transition [7]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
