Inherent Growth Hormone Resistance in the Skeletal Muscle of the Fine Flounder Is Modulated by Nutritional Status and Is Characterized by High Contents of Truncated GHR, Impairment in the JAK2/STAT5 Signaling Pathway, and Low IGF-I Expression

Abstract

A detailed understanding of how the GH and IGF-I regulate muscle growth, especially in early vertebrates, is still lacking. The fine flounder is a flatfish species exhibiting remarkably slow growth, representing an intriguing model for elucidating growth regulatory mechanisms. Key components of the GH system were examined in groups of fish during periods of feeding, fasting, and refeeding. Under feeding conditions, there is an inherent systemic and local (muscle) GH resistance, characterized by higher levels of plasma GH than of IGF-I, skeletal muscle with a greater content of the truncated GH receptor (GHRt) than of full-length GHR (GHRfl), an impaired activation of the Janus kinase 2 (JAK2)-signal transducers and activators of transcription 5 (STAT5) signaling pathway, and low IGF-I expression. Fasting leads to further elevation of plasma GH levels concomitant with suppressed IGF-I levels. The ratio of GHRfl to GHRt in muscle decreases during fasting, causing an inactivation of the JAK2/STAT5 signaling pathway and suppressed IGF-I expression, further impairing growth. When fish are returned to nutritionally favorable conditions, plasma GH levels decrease, and the ratio of GHRfl to GHRt in muscle increases, triggering JAK2/STAT5 reactivation and local IGF-I expression, concomitant with increased growth. The study suggests that systemic IGF-I is supporting basal slow growth in this species, without ruling out that local IGF-I is participating in muscle growth. These results reveal for the first time a unique model of inherent GH resistance in the skeletal muscle of a nonmammalian species and contribute to novel insights of the endocrine and molecular basis of growth regulation in earlier vertebrates.

Dynamic transcriptional regulation of autocrine/paracrine igfbp1, 2, 3, 4, 5, and 6 in the skeletal muscle of the fine flounder during different nutritional statuses

“…Interestingly, contents of igfbp4 and igfbp5 are higher than igfbp2 and igfbp6 at the end of long-term refeeding. These results suggest that different Igfbps might be competing by Igf1, promoting growth, but more attenuated, as has been previously observed in this species full-compensating growth at the end of refeeding (Fuentes et al 2011(Fuentes et al , 2012a.…”

“…Therefore, we suggest that Igf1 would be more available to Igf1r, and PI3K/Akt and MAPK/ERK become strongly reactivated, restoring myogenic activity as we previously reported (Fuentes et al 2011). Thus, in this stage, positive signals may be exceeding negative signals, promoting a strong catchup growth, as is observed during the first stages of refeeding in the fine flounder (Fuentes et al 2011(Fuentes et al , 2012a. During long-term refeeding, low production of local igf1 is restored (Fuentes et al 2012a,b).…”

“…In particular, muscle-derived IGF1 has been proposed as the main regulator of growth in mammals (Sjögren et al 1999, Yakar et al 1999. As in mammals, some recent evidence has shown that in fish, local Igf1 is of importance in muscle growth (Eppler et al 2007, Fox et al 2010, Fuentes et al 2012a. The dynamic of the biological actions of IGFs is modulated by the binding of these growth factors with either specific membrane receptors and/or the IGFBPs.…”

Transcriptional dynamics of immune, growth and stress related genes in skeletal muscle of the fine flounder ( Paralichthys adpersus) during different nutritional statuses

“…Under basal conditions, the fine flounder presents an inherent growth hormone resistance triggering a decrease in muscle IGF-1 expression, resulting in a reduction of skeletal muscle growth (Fuentes et al, 2011(Fuentes et al, , 2012a. This natural resistance makes the fine flounder a unique model for studying mechanisms of muscle atrophy.…”

“…The expression of these molecular markers was then statistically assessed. The fine flounder (Paralichthys adspersus) was used as model species due to its naturally impaired growth rate (Fuentes et al, 2012a and b), with fasting used as a stressor. A close relationship between the fundamental biological processes of stress, the immune system, and growth was found.…”