Expression of insulin growth factor‐1 splice variants and structural genes in rabbit skeletal muscle induced by stretch and stimulation

Abstract

Skeletal muscle is a major source of circulating insulin growth factor‐1 (IGF‐1), particularly during exercise. It expresses two main isoforms. One of the muscle IGF‐1 isoforms (muscle L.IGF‐1) is similar to the main liver IGF‐1 and presumably has an endocrine action. The other muscle isoform as a result of alternative splicing has a different 3′ exon sequence and is apparently designed for an autocrine/paracrine action (mechano‐growth factor, MGF). Using RNase protection assays with a probe that distinguishes these differently spliced forms of IGF‐1, their expression and also the expression of two structural genes was measured in rabbit extensor digitorum longus muscles subjected to different mechanical signals. Within 4 days, stretch using plaster cast immobilization with the limb in the plantar flexed position resulted in marked upregulation of both forms of IGF‐1 mRNA. Electrical stimulation at 10 Hz combined with stretch (overload) resulted in an even greater increase of both types of IGF‐1 transcript, whereas electrical stimulation alone, i.e. without stretch, resulted in no significant increase over muscle from sham‐operated controls. Previously, it was shown that stretch combined with electrical stimulation of the dorsiflexor muscles in the adult rabbit results in a marked increase in muscle mass involving increases in both length and girth, within a few days. The expression of both systemic and autocrine IGF‐1 growth factors provides a link between the mechanical signal and the marked increase in the structural gene expression involved in tissue remodelling and repair. The expression of the β actin gene was seen to be markedly upregulated in the stretched and stretched/stimulated muscles. It was concluded that the increased expression of this cytoskeletal protein gene is an indication that the production of IGF‐1 may initially be a response to local damage. Switches in muscle fibre phenotype were studied using a specific gene probe for the 2X myosin heavy chain gene. Type 2X expression was found to decrease markedly with stimulation alone and when electrical stimulation was combined with stretch. Unlike the induction of IGF‐1 and β actin, the decreased expression of the 2X myosin mRNA was less marked in the ‘stretch only’ muscles. This indicates that the interconversion of fibre type 2X to 2A may in some situations be commensurate with, but not under the control of IGF‐1.

Muscle Force and Power Following Tendon Repair at Altered Tendon Length

“…Increased expression of slow and intermediate MHC isoforms is also observed [14]. Levels of autocrine/paracrine musculotrophic IGF-1 isoforms increase when muscle is chronically stretched [15]. On the contrary, muscle disuse and/or unloading reduces slowoxidative and fast-oxidative MHC content [16].…”

Differential expression of IGF-1 mRNA isoforms in colorectal carcinoma and normal colon tissue

“…Furthermore, peptide Eb, which is composed of Eb1 and Eb2 peptides may exert mitogenic effects on IGF-1 independently; however, the activity of both peptides differs in various types of tissue (28). Peptide Ec (MGF) was originally identified in the liver, while higher amounts have been found in muscle following training (29,30). The isoform plays a critical role in the development, growth and repair of the skeletal muscle (18,29,30) and it protects cardiomyocytes from oxidative and hypertrophic stress via SirT1 activity (31).…”

Differential regulation of Shc adaptor proteins in skeletal muscle, spinal cord and forebrain of aged rats with sensorimotor impairment

“…an aging-related decrease in levels of circulating growth hormone (GH) and liver-derived IGF (reviewed in Hoffman et al, 1997;Cappola et al, 2001). However, a substantial body of evidence shows that muscle may not be dependent on this signalling axis: (i) muscle cells produce both autocrine ('mGF') and circulating isoforms of IGF-1 (reviewed in Goldspink, 1999); (ii) following exercise, circulating IGF-1 derives to a large extent from the muscles rather than the liver (Brahm et al, 1997;McKoy et al, 1999); (iii) tissue-directed mutation of liver igf does not impede postnatal growth of skeletal muscles (Sjogren et al, 1999); (iv) clinical trials with systemic GH and /or IGF treatment have in general failed to increase muscle mass in the elderly (reviewed in Hoffman et al, 1997), whereas (v) target-directed over-expression of IGF-1 in muscle induces hypertrophy and impedes loss of muscle mass in senescence (Barton-Davis et al, 1998;Musaro et al, 2001). Thus, a tentative explanation for the loss of muscle mass may be insufficient activation of the mitogenic /differentiation pathways intrinsic to muscle.…”