Lack of circulating bioactive and immunoreactive IGF-I changes despite improved fitness in chronic kidney disease patients following 48 weeks of physical training
Introduction
The insulin-like growth factor (IGF) system involves IGF-I and six binding proteins that interact with IGF-I to either increase or decrease its bioavailability, thus determining the ability of IGF-I to interact with the IGF-I receptor (IGF-IR) on the cell membranes of target tissues. Of the total circulating IGF-I, ~ 75% is bound in a 150 kDa complex composed of IGF-I, IGFBP-3, and acid labile subunit (ALS), while 20 to 25% is bound in smaller 35 kDa binary complexes, and the remainder (~ 1–2%) is in a free form [1], [2], [3], [4]. When IGF binds to the IGF-IR, a conformational change is induced that stimulates the intracellular kinase domain of the receptor. As a result, tyrosine residues are phosphorylated and the intracellular signal cascade is initiated [5], [6], [7]. The receptor activation may be quantified by an IGF-I bioassay, termed a kinase receptor activation (KIRA) assay, which assesses the ability of serum to activate the receptor in cultured cells at physiological conditions by measuring the phosphorylation of tyrosine residues on the activated receptor [1].
The assessment of bioactive IGF-I is relevant for individuals with chronic kidney disease (CKD) because of the known abnormalities associated with the growth hormone (GH)-IGF-I axis in this patient population [2], [8]. Elevated GH and a concomitant resistance to GH action have been reported in individuals with kidney disease [3]. As IGF-I is known to have anabolic and mitogenic effects [9], reduced bioavailability of IGF-I may be related to impaired muscle protein synthesis and muscle wasting in this population [10]. Interestingly, immunoreactive IGF-I levels have been reported to be in the normal range, while free and bioavailable IGF-I have been reported to be reduced in these individuals [2], [3], [8], [11], [12]. Diminished levels of free and bioactive IGF-I in patients with CKD have been attributed to increased circulating levels of IGFBPs due to reduced clearance with impaired kidney function [2], [8].
Progressive exercise training has been prescribed for individuals with kidney disease in hopes of attenuating or ameliorating the muscle wasting and impaired physical function associated with the condition [13]. The benefits of exercise training may be mediated via alterations and improvements in the IGF system. However, the response of circulating IGF-I to exercise training appears to be variable [9]. As an explanation some studies have suggested that circulating IGF-I exhibits a biphasic response to exercise [4], [14]. Thus in some studies, circulating levels of IGF-I have been reported to decrease following short term exercise training programs, and to increase following longer term programs (> 12 weeks) [12], [14]. It appears, however, counter-intuitively that short-term exercise reduces circulating IGF-I levels and at the same time improves muscular strength, aerobic fitness, and muscle volume. The measurement of bioactive IGF-I using the KIRA method may provide further insight into the response of the IGF-I system to chronic exercise training in CKD patients. Measurement of bioactive IGF-I provides information regarding the interaction between IGF-I and IGFBPs that determines its ability to interact with the IGF-IR. Thus, the purpose of the present study was to assess changes in total IGF-I, IGFBPs, and bioactive IGF-I, as determined by the KIRA method, in stages 3 and 4 CKD patients following a 48-week supervised, progressive physical training program.
Section snippets
Subjects
Patients were recruited and enrolled in the study by physicians and staff at a local nephrology practice based on eligibility criteria, which included being in stage 2 to 4 of the disease (i.e. glomerular filtration rate (GFR) of 0.25 to 1.5 mL s− 1 1.73 m− 2) and taking angiotensin converting enzyme (ACE) inhibitors or angiotensin-receptor blockers. No patient had been participating in a physical training program prior to study commencement. Patients were excluded if they had any contraindications
Results
Baseline clinical and demographic characteristics of the treatment and control groups are presented in Table 1, Table 2. There were no significant differences between treatment and control group for age (p = 0.32), GFR (p = 0.23), or serum creatinine (p = 0.9) at baseline. The average endurance exercise session attendance for the entire 48 weeks was 79.4 ± 16.0% for the treatment group. Energy expenditure during aerobic exercise training sessions was approximately 504.6 ± 352.4 kcal/week at baseline, and
Discussion
The major finding of the present study was that 48 weeks of regular physical exercise training did not result in significant changes in immunoreactive IGF-I, IGF-II, bioactive IGF-I, IGFBP-1, or IGFBP-2 concentrations in stages 3 and 4 CKD patients. Total circulating IGF-I levels correlated positively with measurements of bioactive IGF-I both before and after the 48 week intervention. Despite any significant changes in the IGF-I system, improvements in physical performance measurements were
Acknowledgements
We would like to acknowledge the effort and commitment of the subjects who participated in the study, the student trainers who supervised the training sessions, and the staff at the Springfield College Wellness Center and at Western New England Renal and Transplant Associates (WNERTA) for their accommodation and assistance. We would like to thank Mrs. Lone Kvist, Elsebeth Horneman, Kirsten Nyborg, and Susanne Sørensen for skilled laboratory measurements with the IGF-measurements. This study was
References (28)
- et al.
Serum-free insulin-like growth factor I correlates with clearance in patients with chronic renal failure
Kidney Int.
(1999) - et al.
Role of the time factor in signaling specificity: application to mitogenic and metabolic signaling by the insulin and insulin-like growth factor-I receptor tyrosine kinases
Metabolism
(1995) - et al.
Marked reductions in bioactive insulin-like growth factor-I (IGF-I) during hemodialysis
Growth Horm. IGF Res.
(2010) - et al.
IGF-I system responses during 12 weeks of resistance training in end-stage renal disease patients
Growth Horm. IGF Res.
(2004) - et al.
Exercise ameliorates chronic kidey disease-induced defects in muscle protein metabolism and progenitor cell function
Kidney Int.
(2009) - et al.
Maximal oxygen uptake and nomographic assessment of functional aerobic impairment in cardiovascular disease
Am. Heart J.
(1973) - et al.
A highly sensitive and specific assay for determination of IGF-I bioactivity in human serum
Am. J. Physiol. Endocrinol. Metab.
(2003) - et al.
Growth hormone axis in chronic kidney disease
Pediatr. Nephrol.
(2008) - et al.
Effects of a 9-month strength training intervention on insulin, insulin-like growth factor (IGF-I), IGF-binding protein (IGFBP-1) and IGFBP-3 in 30–50-year old women, Cancer
Epidemiol. Biomark. Prev.
(2002) - et al.
Insulin and insulin-like growth factors stimulate in vivo receptor autophosphorylation and tyrosine phosphorylation of a 70K substrate in cultured fetal chick neurons
Endocrinology
(1991)
The somatomedin hypothesis
Endocr. Rev.
Bioactive rather than total IGF-I is involved in acute responses to nutritional interventions in CAPD patients
Nephrol. Dial. Transplant.
Exercise and the growth hormone-insulin-like growth factor axis
Med. Sci. Sports Exerc.
Protein catabolism in advanced renal disease: role of cytokines
Clin. Nephrol.
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2020, NefrologiaCitation Excerpt :The remaining studies reported not having carried out regular follow-up of the patients during the intervention.13,17,29,32 Glomerular filtration rate was analysed in 11 studies, using the CKD-EPI equation in five of them15,17,19,20,30 and the MDRD (Modification of Diet in Renal Disease) equation in six of them21–23,26,27,33. Proteinuria was studied in six trials: three of them measured it using the albumin to creatinine ratio13,14,21 and three measured 24-hour urinary albumin.16,26,30