Loss of Muscle IGF‐I Production Delays Functional Recovery of Skeletal Muscle Following Disuse

Abstract

PurposeInsulin‐like growth factor‐I (IGF‐I) is an important coordinator of muscle growth, repair, and functional capacity while disuse‐induced skeletal muscle atrophy is a consequence of many diseases and injuries that require prolonged rest. It is known that a lack of muscle activity results in loss of skeletal muscle mass and force generating capacity but it is unclear if locally produced IGF‐I is necessary for recovery from disuse.MethodsMice with muscle‐specific inducible deletion of IGF‐I (MID) and age‐matched controls (CON) underwent hindlimb suspension (HLS) and reloading. Deletion was achieved by the addition of 2mg/mL doxycycline hyclate with 5% sucrose to the mice's drinking water prior to suspension and maintained throughout the course of the experiment. Mice were either left non‐suspended (NS) or suspended for 7 days (SUS) and reloaded for 3 days (Re3), 7 days (Re7), and 14 days (Re14). EDL and soleus muscle function were assessed at each timepoint and tissues were harvested to assess extent of Igf1 deletion, as well as changes in mass, gene expression (qPCR), and IGF‐I content (ELISA). All groups were compared to NS CON mice.ResultsThroughout the duration of the experiment, neither MID or CON mice's body weight changed significantly. During suspension, CON mice exhibited a 20% reduction in soleus mass and no changes for the EDL when normalized to body weight. No normalized mass changes in either muscle were seen in the MID group following suspension. Force generating capacity in CON mice was unaffected by suspension/reloading, while MID mice had a 20 and 23% reduction in specific force for the EDL and soleus, respectively, in SUS and Re7 mice. CON mice showed a reduction of muscle IGF‐I content upon suspension, a marked increase at Re7, and a return to baseline values by Re14. MID mice showed a trend for lower initial IGF‐I levels and remained reduced throughout the course of the experiment. Fiber type distribution and cross‐sectional area did not seem to be significantly affected by Igf1 deletion or suspension/reloading. Fbxo40, Musa1, and Smart expression were unchanged while endogenous Igf1 expression was significantly lower at Re7 in the MID mice compared to CON.ConclusionsWe conclude that a local source of IGF‐I is necessary for muscle recovery from disuse.Support or Funding InformationThis study was supported in part by U54 AR052646This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Kinesin light chain 1 stabilizes insulin receptor substrate 1 to regulate the IGF‐1‐AKT signaling pathway during myoblast differentiation

“…12 Various growth factors, including insulin-like growth factor I (IGF-1), are involved in this process. 13,14 Activated by IGF-1, IGF-1 receptor (IGF-1R) recruits and phosphorylates insulin receptor substrate-1 (IRS1). 15 Serving as a scaffolding adaptor, IRS1 undergoes phase separation to form IGF signalosome and link the IGF-1R to phosphoinositide 3-kinase (PI3K) and protein kinase B (AKT) activation.…”

“…During myogenesis, myoblasts endure a series of genetic reprogramming and morphological changes that form polynuclear myotubes, which then differentiate into mature myofibers 12 . Various growth factors, including insulin‐like growth factor I (IGF‐1), are involved in this process 13,14 . Activated by IGF‐1, IGF‐1 receptor (IGF‐1R) recruits and phosphorylates insulin receptor substrate‐1 (IRS1) 15 .…”