Expression of insulin-like growth factor 1 isoforms in the rabbit oculomotor system

Abstract

Objective The insulin-like growth factor-1 (IGF-1) gene encodes two isoforms, IGF-1Ea and IGF-1Eb. Both isoforms can regulate skeletal muscle growth and strength. It has been suggested that IGF-Eb may be more potent in promoting skeletal muscle hypertrophy. Precise contractile force regulation is particularly important in the oculomotor system. However, expression of these isoforms in mammalian extraocular muscles (EOMs) is unknown. Here, we examined their expression in rabbit EOMs and the innervating nerve, two potential sources for myogenic growth factors, and compared isoform expression between EOMs and limb skeletal muscles. Design Expression of IGF-1 isoforms was quantified by real-time RT-PCR in adult rabbit EOMs, trochlear and ophthalmic nerves, and compared with expression in rabbit limb skeletal muscles. The presence of mature IGF-1 peptide in the muscles was further examined by Western blot. Results Both IGF-1Ea and IGF-1Eb were expressed in the EOM and the trochlear nerve. Both isoforms were expressed at significantly higher levels (9- fold) in EOM than in limb skeletal muscle. Transcripts of IGF-1 isoforms, of IGF-1 receptor and of IGF binding proteins showed a gradient distribution along the EOM from proximal to distal. The mature IGF-1 protein showed the same gradient distribution in the EOM. Conclusions Expression of relatively abundant amounts of both IGF-1 splicing isoforms in EOMs, and at a significantly higher level than in limb skeletal muscle, underscores the potential relevance of these myogenic growth factors in EOM plasticity and force regulation.

Extraocular Muscle Repair and Regeneration

“…This myogenic precursor cell-rich environment may be supported by the maintained expression in adult EOMs of a number of neurotrophic factors that are normally down-regulated in skeletal muscles [75], including insulin-like growth factor-1 and -2 [76, 77], brain derived neurotrophic factor [78, 79], glial derived neurotrophic factor [80, 81], and neurotrophin-3 [78]. All of these neurotrophic factors are critical for maintenance of the ocular motor neurons in development [82, 83].…”

Analysis of spontaneous and nerve-evoked calcium transients in intact extraocular muscles in vitro

“…IGF-1 is expressed at significantly higher levels in EOMs than in other skeletal muscles (Fischer et al, 2002; Feng and von Bartheld, 2011). IGF-1 prevents the age-dependent decrease in charge movement and intracellular calcium in skeletal muscle (Wang et al, 2002), induces intracellular calcium signals (Espinosa et al, 2004), and regulates transcription of dihydropyridine receptors as well as parvalbumin – both of which control calcium (Renganathan et al, 1997; Latres et al, 2005).…”

Effects of sequential injections of hepatocyte growth factor and insulin-like growth factor-I on adult rabbit extraocular muscle

“…Both IGF-I and IGF-I receptor are expressed in extraocular muscle tissue throughout life 2,8 and are thought to play a role in maintaining the continuous myofiber remodeling that occurs in adult mammalian extraocular muscle. 41 Thus the cellular machinery for rapid response to exogenously increased IGF-I is present without requiring receptor up-regulation.…”

“…2,5 This increased muscle force was maintained by sustained delivery of IGF-I to the extraocular muscle, 4 as IGF-I and its receptor are both expressed in adult extraocular muscle. 2,8 There is some concern over the potential effect of high doses of IGF-I in extraocular muscles because recent data has shown a possible link between the IGF-I receptor in orbital fibroblasts in active thyroid eye disease and fat expansion. 9 Thus we tested a strategy for lowering the dosage of IGF-I while maintaining equivalent force augmentation.…”