GH replacement titrated to serum IGF-1 does not reduce concentrations of myostatin in blood or skeletal muscle
Introduction
GH deficiency in adults (GHDA) results in reduced skeletal muscle mass and increased fat mass, both of which are reversed by GH replacement [[1], [2], [3]]. These changes in body composition with GH replacement have been predominantly attributed to the increase in concentrations of IGF-1 in skeletal muscle and blood [1,[4], [5], [6]]. Additionally, GH replacement likely increases skeletal muscle mass by directly decreasing local synthesis of myostatin, a TGFβ family member that is the principal inhibitor of skeletal muscle growth by inhibiting signaling of IGF-1 [[7], [8], [9]]. The actions of GH to inhibit synthesis of myostatin may also mediate the associated reduction in fat mass, because skeletal muscle expression of myostatin is increased with obesity and decreased with weight loss [[10], [11], [12]].
Traditional GH regimens were weight-based with a daily dose of 4–12 μg/kg of recombinant human GH (rhGH), a dosing regimen that has been shown to increase serum concentrations of IGF-1 and decrease myostatin mRNA in skeletal muscles of GHDA [9,13]. However, international guidelines now recommend that GH replacement is started at a low dose and individually titrated to maintain concentrations of IGF-1 within the age- and gender-adjusted reference range [14,15]. Although individually titrated rhGH regimes improve body composition, the increase in muscle mass and decrease in fat mass is likely less than with weight-based rhGH regimes [16]. Currently, it is unclear as to whether circulating concentrations of myostatin are elevated in GH deficiency and decreased by GH replacement, and whether the reduced effectiveness of individually titrated rhGH regimes could be due to ongoing hypersecretion of myostatin. Consequently, the aim of our study was to confirm whether concentrations of myostatin in blood and skeletal muscle are elevated in GH deficiency, and whether these concentrations are reduced by individually titrated regimes of rhGH.
Section snippets
Study participants
Twenty-six adults (≥ 18 years; 18 men and 8 women) with GH deficiency who had been on a stable regimen of pituitary hormone replacement for at least 12 months were recruited through the Waikato Hospital Endocrinology Unit in Hamilton, New Zealand. GH deficiency was defined as peak plasma GH concentrations <5.0 μg/L following an insulin tolerance test and/or < 3.0 μg/L on a glucagon stimulation test [17]. All participants had a peak plasma GH concentration ≤ 1.7 μg/L and all but two participants
Results
Characteristics, pituitary hormone profile, and physical and metabolic parameters of study participants are outlined in Table 2. Of note, participants in the rhGH group were older and had a higher BMI and waist to hip ratio than healthy controls (P < .05). There were no significant differences in fasting concentrations of total testosterone, FT4, cortisol, glucose, and HbA1c between groups. There were also no significant changes in these biochemical markers or physical parameters in the rhGH
Discussion
We have demonstrated that myostatin concentrations are elevated in both blood and skeletal muscle in GH deficient adults. However, in contrast to a 5 μg/kg/day regimen, we show that GH replacement titrated to serum concentrations of IGF-1 do not reduce these elevated concentrations of myostatin in either blood or skeletal muscle [9]. Our finding that a mean rhGH dose of 3 μg/kg/day restored concentrations of IGF-1 in both blood and skeletal muscle, suggests that a higher dose of rhGH is
Acknowledgements
The authors thank Tania Yarndley for her assistance with the skeletal muscle biopsies, and Amy Gaskell for her assistance with statistical analysis. We wish to thank all the study participants. This work was supported by grants from the Waikato Medical Research Foundation and the Royal Australasian College of Physicians.
Conflict of interest statement
The authors have no conflict of interest and nothing to disclose.
Disclosure statement
The authors have nothing to disclose.
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