Abstract
Purpose
While growth hormone (GH) and the insulin-like growth factor type I (IGF-I) are known to exert synergistic actions on muscle anabolism, the consequences of prolonged GH deficiency (GHD) on muscle function have not been well defined. We have previously described a large cohort of subjects with isolated GHD (IGHD) caused by a mutation in the GH-releasing hormone receptor gene, with low serum levels of GH and IGF-I. The aim of this study was to assess muscular function in these IGHD subjects.
Methods
A total of 31 GH-naïve IGHD (16 males) and 40 control (20 males) subjects, matched by age and degree of daily physical activity, were enrolled. Fat free mass was measured by bioelectrical impedance; muscle strength by dynamometry of handgrip, trunk extension, and knee extension; myoelectric activity and muscle fatigue by fractal dimension; conduction velocity in vastus medialis, rectus femoris, and vastus lateralis muscles by surface electromyography.
Results
The IGHD group showed higher knee extension strength both when corrected for weight and fat free mass, and higher handgrip and trunk extension strength corrected by fat free mass. They also exhibit higher conduction velocity of the muscles vastus medialis, rectus femoris, and vastus lateralis, but lower free fat mass and myoelectric activity of the vastus medialis, rectus femoris and vastus lateralis. There were no differences between the two groups in fractal dimension in all studied muscles.
Conclusion
Individuals with untreated IGHD have better muscle strength parameters adjusted for weight and fat free mass than controls. They also exhibit greater peripheral resistance to fatigue, demonstrating satisfactory muscle function.
Similar content being viewed by others
References
J. Trezise, N. Collier, A.J. Blazevich, Anatomical and neuromuscular variables strongly predict maximum knee extension torque in healthy men. Eur. J. Appl. Physiol. 116, 1159–1177 (2016)
T.S. Gross, S.L. Poliachik, J. Prasad, S.D. Bain, The effect of muscle dysfunction on bone mass and morphology. J. Musculoskelet. Neuron. Interact. 10, 25–34 (2010)
J.B. Tyrovola, The ‘Mechanostat’ principle and the osteoprotegerin-OPG/RANKL/RANK system PART II. The role of the hypothalamic - pituitary axis. J. Cell. Biochem. 966, 1–20 (2016)
Y.H. Song, J.L. Song, P. Delafontaine, M.P. Godard, The therapeutic potential of IGF-I in skeletal muscle repair. Trends Endocrinol. Metab. 24, 310–319 (2013)
C.Q. Gao, R. Zhi, Z. Yang, H.C. Li, H.C. Yan, X.Q. Wang, Low dose of IGF-I increases cell size of skeletal muscle satellite cells via Akt/S6K signaling pathway. J. Cell. Biochem. 116, 2637–2648 (2015)
J.C. Chow, P.R. Ling, Z. Qu, L. Laviola, A. Ciccarone, B.R. Bistrian, R.J. Smith, Growth hormone stimulates tyrosine phosphorylation of JAK2 and STAT5, but not insulin receptor substrate-1 or SHC proteins in liver and skeletal muscle of normal rats in vivo. Endocrinology 137, 2880–2886 (1996)
X. Ge, J. Yu, H. Jiang, Growth hormone stimulates protein synthesis in bovine skeletal muscle cells without altering insulin-like growth factor-I mRNA expression. J. Anim. Sci. 90, 1126–1133 (2012)
V. Chikani, K.K.Y. Ho, Action of GH on skeletal muscle function: molecular and metabolic mechanisms. J. Mol. Endocrinol. 52, 107–123 (2013)
Y. Wang, D.D. Bikle, W. Chang, Autocrine and paracrine actions of IGF-I signaling in skeletal development. Bone Res. 1, 249–259 (2013)
D.D. Bikle, C. Tahimic, W. Chang, Y. Wang, A. Philippou, E.R. Barton, Role of IGF-I signaling in muscle bone interactions. Bone 80, 79–88 (2015)
D.S. Kim, E. Itoh, K. Iida, M.O. Thorner, Growth hormone icreases mRNA Levels of PPAR δ and Foxo1 in skeletal muscle of growth hormone deficient lit / lit mice. Endocr. J. 56, 141–147 (2009)
E.O. List, L. Sackmann-Sala, D.E. Berryman, K. Funk, B. Kelder, E.S. Gosney, S. Okada, J. Ding, D. Cruz-Topete, J.J. Kopchick, Endocrine parameters and phenotypes of the growth hormone receptor gene disrupted (GHR−/−) mouse. Endocr. Rev. 32, 356–386 (2011)
K.T. Coschigano, A.N. Holland, M.E. Riders, E.O. List, A. Flyvbjerg, J.J. Kopchick, Deletion, but not antagonism, of the mouse growth hormone receptor results in severely decreased body weights, insulin, and insulin-like growth factor I levels and increased life span. Endocrinology 144, 3799–3810 (2003)
R. Basu, Y. Qian, J.J. Kopchick, Mechanisms in endocrinology: lessons from growth hormone receptor gene disrupted mice: are there benefits of endocrine defects? Eur. J. Endocrinol. 181, 155–181 (2018)
S. Shibata, C. Ueno, T. Ito, K. Yamanouchi, T. Matsuwaki, M. Nishihara, Skeletal muscle growth defect in human growth hormone transgenic rat is accompanied by phenotypic changes in progenitor cells. Age 32, 239–253 (2010)
N. Improda, D. Capalbo, A. Esposito, M. Salerno, Muscle and skeletal health in children and adolescents with GH deficiency. Best. Pract. Res. Clin. Endocrinol. Metab. 30, 771–783 (2016)
L.J. Woodhouse, A. Mukherjee, S.M. Shalet, S. Ezzat, The influence of growth hormone status on physical impairments, functional limitations, and health-related quality of life in adults. Endocr. Rev. 27, 287–317 (2006)
A. Sartorio, F. Agosti, A.D. Col, G. Mazzilli, N. Marazzi, C. Busti, R. Galli, C.L. Lafortuna, Muscle strength and power, maximum oxygen consumption, and body composition in middle-aged short-stature adults with childhood-onset growth harmone deficiency. Arch. Med. Res. 39, 78–83 (2008)
W.M. Widdowson, J. Gibney, The effect of growth hormone (GH) replacement on muscle strength in patients with GH-deficiency: A meta-analysis. Clin. Endocrinol. (Oxf.). 72, 787–792 (2010)
M.J. Modesto, N.M. Amer, O. Erichsen, S. Hernandez, C.D. Santos, J.A.R. Carvalho, R.M. Pereira, S.N. França, L. Lacerda, Muscle strength and body composition during the transition phase in patients treated with recombinant GH to final height. J. Pediatr. Endocrinol. Metab. 27, 813–820 (2014)
K. Hermansen, M. Bengtsen, M. Kjær, P. Vestergaard, J.O.L. Jørgensen, Impact of GH administration on athletic performance in healthy young adults: a systematic review and meta-analysis of placebo-controlled trials. Growth Horm. IGF Res. 34, 38–44 (2017)
R. Salvatori, C.Y. Hayashida, M.H. Aguiar-Oliveira, J.A. Phillips, A.H.O. Souza, R.G. Gondo, S.P.A. Toledo, M.M. Conceicão, M. Prince, H.G. Maheshwari, G. Baumann, M.A. Levine, Familial dwarfism due to a novel mutation of the growth hormone-releasing hormone receptor gene. J. Clin. Endocrinol. Metab. 84, 917–923 (1999)
M.H. Aguiar-Oliveira, M.S. Gill, F. Miraki-Moud, C.A. Menezes, A.H.O. Souza, C.E. Martinelli, F.A. Pereira, R. Salvatori, M.A. Levine, S.M. Shalet, C. Camacho-Hubner, P.E. Clayton, Effect of severe growth hormone (GH) deficiency due to a mutation in the GH-releasing hormone receptor on Insulin-Like Growth Factors (IGFs), IGF-Binding Proteins, and Ternary Complex Formation Throughout Life. J. Clin. Endocrinol. Metab. 84, 4118–4126 (1999)
M.H. Aguiar-Oliveira, A.H.O. Souza, C.R.P. Oliveira, V.C. Campos, L.A. Oliveira-Neto, R. Salvatori, The multiple facets of GHRH/GH/IGF-I axis: lessons from lifetime, untreated, isolated GH deficiency due to a GHRH receptor gene mutation. Eur. J. Endocrinol. 177, 85–97 (2017)
M.B. Gois-Junior, R. Salvatori, M.H. Aguiar-Oliveira, F.A. Pereira, C.R.P. Oliveira, L.A. Oliveira-Neto, R.M.C. Pereira, A.H.O. Souza, E.V. Melo, F.J.A. Paula, The consequences of growth hormone-releasing hormone receptor haploinsufficiency for bone quality and insulin resistance. Clin. Endocrinol. (Oxf.). 77, 379–384 (2012)
C.C. Epitácio-Pereira, G.M.F. Silva, R. Salvatori, J.A.M. Santana, F.A. Pereira, M.B. Gois-Junior, A.V.O. Britto, C.R.P. Oliveira, A.H.O. Souza, E.G. Santos, V.C. Campos, R.M.C. Pereira, E.H.O. Valença, R.A.A. Barbosa, M.I.T. Farias, F.J.A. Paula, T.V. Ribeiro, M.C.P. Oliveira, M.H. Aguiar-Oliveira, Isolated GH deficiency due to a GHRH receptor mutation causes hip joint problems and genu valgum, and reduces size but not density of trabecular and mixed bone. J. Clin. Endocrinol. Metab. 98, 1710–1715 (2013)
J.A.R. Barbosa, R. Salvatori, C.R.P. Oliveira, R.M.C. Pereira, C.T. Farias, A.V.O. Britto, N.T. Farias, A. Blackford, M.H. Aguiar-Oliveira, Quality of life in congenital, untreated, lifetime isolated growth hormone deficiency. Psychoneuroendocrinology 34, 894–900 (2009)
M.H. Aguiar-Oliveira, F.T. Oliveira, R.M.C. Pereira, C.R.P. Oliveira, A. Blackford, E.H.O. Valenca, E.G. Santos, M.B. Gois-Junior, R.A. Meneguz-Moreno, V.P. Araujo, L.A. Oliveira-Neto, R.P. Almeida, M.A. Santos, N.T. Farias, D.C.R. Silveira, G.W. Cabral, F.R. Calazans, J.D. Seabra, T.F. Lopes, E.O. Rodrigues, L.A. Porto, I.P. Oliveira, E.V. Melo, M. Martari, R. Salvatori, Longevity in untreated congenital growth hormone deficiency due to a homozygous mutation in the GHRH receptor gene. J. Clin. Endocrinol. Metab. 95, 714–721 (2010)
World Health Organization - Measuring obesity: classification, and description of anthropometric data. Copenhagen: World Health Organization. 1988.
IPAQ Research Committee. Guidelines for data processing and analysis of the international physical activity questionnaire (IPAQ) short and long forms. In: International physical activity questionnaire (2005)
J.R. Moon, J.R. Stout, A.E. Smith-Ryan, K.L. Kendall, D.H. Fukuda, J.T. Cramer, S.E. Moon, Tracking fat-free mass changes in elderly men and women using single-frequency bioimpedance and dual-energy X-ray absorptiometry: a four-compartment model comparison. Eur. J. Clin. Nutr. 67, 40–46 (2013)
U.G. Kyle, I. Bosaeus, A.D. Lorenzo, P. Deurenberg, M. Elia, J.M. Gómez, B.L. Heitmann, L. Kent-Smith, J.C. Melchior, M. Pirlich, H. Scharfetter, A.M.W.J. Schols, C. Pichard, Bioelectrical impedance analysis - Part I: review of principles and methods. Clin. Nutr. 23, 1226–1243 (2004)
G. Sergi, M. Rui, B. Stubbs, N. Veronese, E. Manzato, Measurement of lean body mass using bioelectrical impedance analysis: a consideration of the pros and cons. Aging Clin. Exp. Res. 29, 591–597 (2017)
S.R. Silva, T.H. Nakagawa, A.L.G. Ferreira, L.C. Garcia, J.E.M. Santos, F.V. Serrão, Lower limb strength and flexibility in athletes with and without patellar tendinopathy. Phys. Ther. Sport. 20, 19–25 (2016)
Fess E.: Grip strength. Clinical assessment recommendations. American Society of Hand Therapists. 41–45. Chicago (1992)
F.L.F. Eichinger, A.V. Soares, J.M. Carvalho, M.S. Gevaerd, S.C. Domenech, N.G. Borges, Dinamometria lombar: Um teste funcional para o tronco. Rev. Bras. Med Trab. 14, 120–126 (2016)
S. Dorsch, L. Ada, C.G. Canning, Lower limb strength is significantly impaired in all muscle groups in ambulatory people with chronic stroke: a cross-sectional study. Arch. Phys. Med. Rehabil. 97, 522–527 (2016)
U. Grevstad, P. Jæger, J.K. Sørensen, B. Gottschau, B. Ilfeld, M. Ballegaard, M. Hagelskjaer, J.B. Dahl, The effect of local anesthetic volume within the adductor canal on quadriceps femoris function evaluated by electromyography: a randomized, observer- and infject-blinded, placebo-controlled study in volunteers. Anesth. Analg. 123, 493–500 (2016)
H.J. Hermens, B. Freriks, C. Disselhorst-Klug, G. Rau, Development of recommendations for SEMG sensors and sensor placement procedures. J. Electromyogr. Kinesiol. 10, 361–374 (2000)
D.M. Pincivero, R.C. Green, J.D. Mark, R.M. Campy, Gender and muscle differences in EMG amplitude and median frequency, and variability during maximal voluntary contractions of the quadriceps femoris. J. Electromyogr. Kinesiol. 10, 189–196 (2000)
E.C. Conchola, R.M. Thiele, T.B. Palmer, D.B. Smith, B.J. Thompson, Effects of neuromuscular fatigue on electromechanical delay of the leg extensors and flexors in young men and women. Muscle Nerve 52, 844–851 (2015)
M.W. Buckthorpe, R. Hannah, T.G. Pain, J.P. Folland, Reliability of neuromuscular measurements during explosive isometric contractions, with special reference to electromyography normalization techniques. Muscle Nerve 46, 566–576 (2012)
M. Beretta-Piccoli, G. D’Antona, M. Barbero, B. Fisher, C.M. Dieli-Conwright, R. Clijsen, C. Cescon, Evaluation of central and peripheral fatigue in the quadriceps using fractal dimension and conduction velocity in young females. PLoS. One. 10, 1–15 (2015)
E. Hohenauer, C. Cescon, T. Deliens, P. Clarys, R. Clijsen, The effect of local skin cooling before a sustained, submaximal isometric contraction on fatigue and isometric quadriceps femoris performance: a randomized controlled trial. J. Therm. Biol. 65, 88–94 (2017)
J.A.S. Barreto-Filho, M.R.S. Alcantara, R. Salvatori, M.A. Barreto, A.C.S. Sousa, V. Bastos, A.H. Souza, R.M.C. Pereira, P.E. Clayton, M.S. Gill, M.H. Aguiar-Oliveira, Familial isolated growth hormone deficiency is associated with increased systolic blood pressure, central obesity and dyslipidemia. J. Clin. Endocrinol. Metab. 87, 2018–2023 (2002)
R.C. Cuneo, F. Salomon, M. Wiles, P.H. Sönksen, Skeletal muscle performance in adults with growth hormone deficiency. Horm. Res. 33, 55–60 (1990)
A.R. Hoffman, J.E. Kuntze, J. Baptista, H.B.A. Baum, G.P. Baumann, B.M.K. Biller, R.V. Clark, D. Cook, S.E. Inzucchi, D. Kleinberg, A. Klibanski, L.S. Phillips, E.C. Ridgway, R.J. Robbins, J. Schlechte, M. Sharma, M.O. Thorner, M.L. Vance, Growth hormone (GH) replacement therapy in adult-onset gh deficiency: effects on body composition in men and women in a double-blind, randomized, placebo-controlled trial. J. Clin. Endocrinol. Metab. 89, 2048–2056 (2004)
S. Gonzalez, T. Sathyapalan, Z. Javed, S.L. Atkin, Effects of growth hormone replacement on peripheral muscle and exercise capacity in severe growth hormone deficiency. Front Endocrinol. (Lausanne). 8, 1–7 (2018)
G. Gotherstrom, M. Elbornsson, K. Stibrant-Sunnerhagen, B.A. Bengtsson, G. Johannsson, J. Svensson, Muscle strength in elderly adults with GH deficiency after 10 years of GH replacement. Eur. J. Endocrinol. 163, 207–215 (2010)
W.M. Widdowson, J. Gibney, The effect of growth hormone replacement on exercise capacity in patients with GH deficiency: a metaanalysis. J. Clin. Endocrinol. Metab. 93, 4413–4417 (2008)
R. Borde, T. Hortobágyi, U. Granacher, Dose–response relationships of resistance training in healthy old adults: a systematic review and meta-analysis. Sports Med. 45, 1693–1720 (2015)
T.M. Manini, B.C. Clark, Dynapenia and aging: an update. J. Gerontol. A. Biol. Sci. Med. Sci. 67, 28–40 (2012)
García-Hermoso A., Cavero-Redondo I., Ramírez-Vélez R., Ruiz J. R., Ortega F. B., Lee D. C., Martínez-Vizcaíno V.: Muscular strength as a predictor of all-cause mortality in an apparently healthy population: a systematic review and meta-analysis of data from approximately 2 million men and women. Arch Phys Med Rehabil. https://doi.org/10.1016/j.apmr.2018.01.008
I.C. Van-Nieuwpoort, M.C. Vlot, L.A. Schaap, P. Lips, M.L. Drent, The relationship between serum IGF-1, handgrip strength, physical performance and falls in elderly men and women. Eur. J. Endocrinol. 179, 73–84 (2018)
M.V. Narici, H. Hoppeler, B. Kayser, L. Landoni, H. Claassen, C. Gavardi, M. Conti, P. Cerretelli, Human quadriceps cross-sectional area, torque and neural activation during 6 months strength training. Acta Physiol. Scand. 157, 175–186 (1996)
C.J. Luca, The use of surface electromyography in biomechanics. J. Appl. Bio. 13, 135–163 (1997)
A. Sinha, K.G. Hollingsworth, S. Ball, T. Cheetham, Impaired quality of life in growth hormone-deficient adults is independent of the altered skeletal muscle oxidative metabolism found in conditions with peripheral fatigue. Clin. Endocrinol. (Oxf.). 80, 107–114 (2014)
E. Shurka, Z. Laron, Adjustment and rehabilitation problems of children and adolescents with growth retardation. I. Familial dwarfism with high plasma immunoreactive human growth hormone. Isr. J. Med. Sci. 11, 352–357 (1975)
Laron Z.: Muscle force and endurance in untreated adult and IGF-I treated children with laron syndrome. In Iaron syndrome - from man to mouse, pp. 161–164. Springer Berlin Heidelberg (2011)
S. Leone, A. Chiavaroli, R. Shohreh, C. Ferrante, A. Ricciuti, F. Manippa, L. Recinella, C.D. Nisio, G. Orlando, R. Salvatori, M. Vacca, L. Brunetti, Increased locomotor and thermogenic activity in mice with targeted ablation of the GHRH gene. Growth Horm. IGF Res. 25, 80–84 (2015)
Acknowledgements
The authors thank the Associação do Crescimento Físico e Humano de Itabaianinha, for assistance.
Funding
This work was not supported by public or private funds.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethical approval
All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.
Conflict of interest
The authors declare that there is no conflict of interest.
Rights and permissions
About this article
Cite this article
Andrade-Guimarães, A.L., Aguiar-Oliveira, M.H., Salvatori, R. et al. Adult individuals with congenital, untreated, severe isolated growth hormone deficiency have satisfactory muscular function. Endocrine 63, 112–119 (2019). https://doi.org/10.1007/s12020-018-1763-5
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s12020-018-1763-5