Irisin Serum Levels and Skeletal Muscle Assessment in a Cohort of Charcot-Marie-Tooth Patients

Graziana Colaianni, Angela Oranger, Manuela Dicarlo, Roberto Lovero, Giuseppina Storlino, Patrizia Pignataro, Antonietta Fontana, Francesca Di Serio, Angelica Ingravallo, Giuseppe Caputo, Alfredo Di Leo, Michele Barone, Maria Grano, Graziana Colaianni, Angela Oranger, Manuela Dicarlo, Roberto Lovero, Giuseppina Storlino, Patrizia Pignataro, Antonietta Fontana, Francesca Di Serio, Angelica Ingravallo, Giuseppe Caputo, Alfredo Di Leo, Michele Barone, Maria Grano

Abstract

Background: Charcot-Marie-Tooth (CMT) indicates a group of inherited polyneuropathies whose clinical phenotypes primarily include progressive distal weakness and muscle atrophy. Compelling evidence showed that the exercise-mimetic myokine irisin protects against muscle wasting in an autocrine manner, thus possibly preventing the onset of musculoskeletal atrophy. Therefore, we sought to determine if irisin serum levels correlate with biochemical and muscle parameters in a cohort of CMT patients.

Methods: This cohort study included individuals (N=20) diagnosed with CMT disease. Irisin and biochemical markers were quantified in sera. Skeletal muscle mass (SMM) was evaluated by bioelectric impedance analysis, muscle strength by handgrip, and muscle quality was derived from muscle strength and muscle mass ratio.

Results: CMT patients (m/f, 12/8) had lower irisin levels than age and sex matched healthy subjects (N=20) (6.51 ± 2.26 vs 9.34 ± 3.23 μg/ml; p=0.003). SMM in CMT patients was always lower compared to SMM reference values reported in healthy Caucasian population matched for age and sex. Almost the totality of CMT patients (19/20) showed low muscle quality and therefore patients were evaluated on the basis of muscle strength. Irisin was lower in presence of pathological compared to normal muscle strength (5.56 ± 1.26 vs 7.67 ± 2.72 μg/ml; p=0.03), and directly correlated with the marker of bone formation P1PN (r= 0.669; 95%CI 0.295 to 0.865; p=0.002), but inversely correlated with Vitamin D (r=-0.526; 95%CI -0,791 to -0,095; p=0.017). Surprisingly, in women, irisin levels were higher than in men (7.31 ± 2.53 vs 5.31 ± 1.02 μg/ml, p=0.05), and correlated with both muscle strength (r=0.759; 95%CI 0.329 to 0.929; p=0.004) and muscle quality (r=0.797; 95%CI 0.337 to 0.950; p=0.006).

Conclusion: Our data demonstrate lower irisin levels in CMT patients compared to healthy subjects. Moreover, among patients, we observed, significantly higher irisin levels in women than in men, despite the higher SMM in the latter. Future studies are necessary to establish whether, in this clinical contest, irisin could represent a marker of the loss of muscle mass and strength and/or bone loss.

Trial registration: ClinicalTrials.gov NCT04786522.

Keywords: CMT; irisin; muscle atrophy; myokine; osteoporosis.

Conflict of interest statement

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Copyright © 2022 Colaianni, Oranger, Dicarlo, Lovero, Storlino, Pignataro, Fontana, Di Serio, Ingravallo, Caputo, Di Leo, Barone and Grano.

Figures

Figure 1
Figure 1
Irisin serum levels are significantly lower in CMT patients (N = 20) compared to healthy matched controls (N = 20); p values as indicated.
Figure 2
Figure 2
CMT patients with pathological muscle strength (N = 11) show lower Irisin levels than CMT patients with normal muscle strength (N = 9) (A). Muscle quality is lower in CMT patients with pathological muscle strength (N = 11) than CMT patients with normal muscle strength (N = 9) (B). Data are presented as box-and-whisker plots with median and interquartile ranges, from max to min, with all data points shown.
Figure 3
Figure 3
Negative correlation between Irisin and 25(OH)-Vitamin D serum levels in CMT patients with Vitamin D deficiency (N = 19) (A). Irisin serum levels negatively correlated with 25(OH)-Vitamin D in CMT patients with pathologic handgrip (N = 11) (B). Linear regression, r and p values as indicated.
Figure 4
Figure 4
Linear regression (r and p values as indicated) showing positive correlation between Irisin and the bone formation marker P1PN in all CMT patients (N=20) (A) and in CMT patients with normal muscle strength (N=9) (B).
Figure 5
Figure 5
Circulating Irisin levels are higher in female CMT patients (N = 12) than in male (N = 8) (A). Data are presented as box-and-whisker plots with median and interquartile ranges, from max to min, with all data points shown. In female CMT patients, Irisin positively correlated with muscle strength (B), muscle quality (C), and myoglobin (D). Linear regression, r and p values as indicated.

References

    1. Szigeti K, Lupski JR. Charcot-Marie-Tooth Disease. Eur J Hum Genet (2009) 17(6):703–10. doi: 10.1038/ejhg.2009.31
    1. Hoyle JC, Isfort MC, Roggenbuck J, Arnold WD. The Genetics of Charcot-Marie-Tooth Disease: Current Trends and Future Implications for Diagnosis and Management. Appl Clin Genet (2015) 8:235–43. doi: 10.2147/TACG.S69969
    1. Saporta AS, Sottile SL, Miller LJ, Feely SM, Siskind CE, Shy ME. Charcot-Marie-Tooth Disease Subtypes and Genetic Testing Strategies. Ann Neurol (2011) 69(1):22–33. doi: 10.1002/ana.22166
    1. Stavrou M, Sargiannidou I, Georgiou E, Kagiava A, Kleopa KA. Emerging Therapies for Charcot-Marie-Tooth Inherited Neuropathies. Int J Mol Sci (2021) 22(11):6048. doi: 10.3390/ijms22116048
    1. Corrado B, Ciardi G, Bargigli C. Rehabilitation Management of the Charcot-Marie-Tooth Syndrome: A Systematic Review of the Literature Vol. 95. Medicine (Baltimore; ) Published by Wolters Kluwer Health (Philadelphia, PA) (2016). doi: 10.1097/MD.0000000000003278
    1. Garber CE, Blissmer B, Deschenes MR, Franklin BA, Lamonte MJ, Lee IM, et al. . American College of Sports Medicine. American College of Sports Medicine Position Stand. Quantity and Quality of Exercise for Developing and Maintaining Cardiorespiratory, Musculoskeletal, and Neuromotor Fitness in Apparently Healthy Adults: Guidance for Prescribing Exercise. Med Sci Sports Exerc (2011) 43(7):1334–59. doi: 10.1249/MSS.0b013e318213fefb
    1. Ma J, Chen K. The Role of Irisin in Multiorgan Protection. Mol Biol Rep (2021) 48(1):763–72. doi: 10.1007/s11033-020-06067-1
    1. Maak S, Norheim F, Drevon CA, Erickson HP. Progress and Challenges in the Biology of FNDC5 and Irisin. Endocr Rev (2021) 42(4):436–56. doi: 10.1210/endrev/bnab003
    1. Colaianni G, Storlino G, Sanesi L, Colucci S, Grano M. Myokines and Osteokines in the Pathogenesis of Muscle and Bone Diseases. Curr Osteoporos Rep (2020) 18(4):401–7. doi: 10.1007/s11914-020-00600-8
    1. Colaianni G, Cuscito C, Mongelli T, Pignataro P, Buccoliero C, Liu P, et al. . The Myokine Irisin Increases Cortical Bone Mass. Proc Natl Acad Sci USA (2015) 112(39):12157–62. doi: 10.1073/pnas.1516622112
    1. Colaianni G, Notarnicola A, Sanesi L, Brunetti G, Lippo L, Celi M, et al. . Irisin Levels Correlate With Bone Mineral Density in Soccer Players. J Biol Regul Homeost Agents (2017) 31(4 suppl 1):21–8.
    1. Colaianni G, Faienza MF, Sanesi L, Brunetti G, Pignataro P, Lippo L, et al. . Irisin Serum Levels Are Positively Correlated With Bone Mineral Status in a Population of Healthy Children. Pediatr Res (2019) 85(4):484–8. doi: 10.1038/s41390-019-0278-y
    1. Faienza MF, Brunetti G, Sanesi L, Colaianni G, Celi M, Piacente L, et al. . High Irisin Levels Are Associated With Better Glycemic Control and Bone Health in Children With Type 1 Diabetes. Diabetes Res Clin Pract (2018) 141:10–7. doi: 10.1016/j.diabres.2018.03.046
    1. Palermo A, Sanesi L, Colaianni G, Tabacco G, Naciu AM, Cesareo R, et al. . A Novel Interplay Between Irisin and PTH: From Basic Studies to Clinical Evidence in Hyperparathyroidism. J Clin Endocrinol Metab (2019) 104(8):3088–96. doi: 10.1210/jc.2018-02216
    1. Colaianni G, Errede M, Sanesi L, Notarnicola A, Celi M, Zerlotin R, et al. . Irisin Correlates Positively With BMD in a Cohort of Older Adult Patients and Downregulates the Senescent Marker P21 in Osteoblasts. J Bone Miner Res (2021) 36(2):305–14. doi: 10.1002/jbmr.4192
    1. Colaianni G, Mongelli T, Cuscito C, Pignataro P, Lippo L, Spiro G, et al. . Irisin Prevents and Restores Bone Loss and Muscle Atrophy in Hind-Limb Suspended Mice. Sci Rep (2017) 7(1):2811. doi: 10.1038/s41598-017-02557-8
    1. Reza MM, Subramaniyam N, Sim CM, Ge X, Sathiakumar D, McFarlane C, et al. . Irisin Is a Pro-Myogenic Factor That Induces Skeletal Muscle Hypertrophy and Rescues Denervation-Induced Atrophy. Nat Commun (2017) 8(1):1104. doi: 10.1038/s41467-017-01131-0
    1. Chang JS, Kim TH, Nguyen TT, Park KS, Kim N, Kong ID. Circulating Irisin Levels as a Predictive Biomarker for Sarcopenia: A Cross-Sectional Community-Based Study. Geriatr Gerontol Int (2017) 17(11):2266–73. doi: 10.1111/ggi.13030
    1. Park HS, Kim HC, Zhang D, Yeom H, Lim SK. The Novel Myokine Irisin: Clinical Implications and Potential Role as a Biomarker for Sarcopenia in Postmenopausal Women. Endocrine (2019) 64(2):341–8. doi: 10.1007/s12020-018-1814-y
    1. Qaisar R, Karim A, Muhammad T, Shah I, Khan J. Prediction of Sarcopenia Using a Battery of Circulating Biomarkers. Sci Rep (2021) 11(1):8632. doi: 10.1038/s41598-021-87974-6
    1. Viggiani MT, Lorusso O, Natalizio F, Principi M, Di Leo A, Barone M. Influence of Chemotherapy on Total Energy Expenditure in Patients With Gastrointestinal Cancer: A Pilot Study. Nutrition (2017) 42:7–11. doi: 10.1016/j.nut.2017.05.001
    1. Roberts HC, Denison HJ, Martin HJ, Patel HP, Syddall H, Cooper C, et al. . A Review of the Measurement of Grip Strength in Clinical and Epidemiological Studies: Towards a Standardised Approach. Age Ageing (2011) 40(4):423–9. doi: 10.1093/ageing/afr051
    1. Mathiowetz V. Effects of Three Trials on Grip and Pinch Strength Measurements. J Handb Ther (1990) 3:195–8. doi: 10.1016/S0894-1130(12)80377-2
    1. Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, et al. . Sarcopenia: Revised European Consensus on Definition and Diagnosis. Age Ageing (2019) 48(1):16–31. doi: 10.1093/ageing/afy169
    1. Janssen I, Heymsfield SB, Wang ZM, Ross R. Skeletal Muscle Mass and Distribution in 468 Men and Women Aged 18-88 Yr. J Appl Physiol (1985) (2000) 89(1):81–8. doi: 10.1152/jappl.2000.89.1.81
    1. Beaudart C, Buckinx F, Rabenda V, Gillain S, Cavalier E, Slomian J, et al. . The Effects of Vitamin D on Skeletal Muscle Strength, Muscle Mass, and Muscle Power: A Systematic Review and Meta-Analysis of Randomized Controlled Trials. J Clin Endocrinol Metab (2014) 99(11):4336–45. doi: 10.1210/jc.2014-1742
    1. Bergen HR, 3rd, Farr JN, Vanderboom PM, Atkinson EJ, White TA, Singh RJ, et al. . Myostatin as a Mediator of Sarcopenia Versus Homeostatic Regulator of Muscle Mass: Insights Using a New Mass Spectrometry-Based Assay. Skelet Muscle (2015) 5:21. doi: 10.1186/s13395-015-0047-5
    1. Levinger I, Scott D, Nicholson GC, Stuart AL, Duque G, McCorquodale T, et al. . Undercarboxylated Osteocalcin, Muscle Strength and Indices of Bone Health in Older Women. Bone (2014) 64:8–12. doi: 10.1016/j.bone.2014.03.008
    1. Szulc P, Naylor K, Hoyle NR, Eastell R, Leary ET, National Bone Health Alliance Bone Turnover Marker Project . Use of CTX-I and PINP as Bone Turnover Markers: National Bone Health Alliance Recommendations to Standardize Sample Handling and Patient Preparation to Reduce Pre-Analytical Variability. Osteoporos Int (2017) 28(9):2541–56. doi: 10.1007/s00198-017-4082-4
    1. Tazir M, Hamadouche T, Nouioua S, Mathis S, Vallat JM. Hereditary Motor and Sensory Neuropathies or Charcot-Marie-Tooth Diseases: An Update. J Neurol Sci (2014) 347(1-2):14–22. doi: 10.1016/j.jns.2014.10.013
    1. Shan T, Liang X, Bi P, Kuang S. Myostatin Knockout Drives Browning of White Adipose Tissue Through Activating the AMPK-Pgc1α-Fndc5 Pathway in Muscle. FASEB J (2013) 27(5):1981–9. doi: 10.1096/fj.12-225755
    1. Huh JY, Dincer F, Mesfum E, Mantzoros CS. Irisin Stimulates Muscle Growth-Related Genes and Regulates Adipocyte Differentiation and Metabolism in Humans. Int J Obes (Lond) (2014) 38(12):1538–44. doi: 10.1038/ijo.2014.42
    1. Planella-Farrugia C, Comas F, Sabater-Masdeu M, Moreno M, Moreno-Navarrete JM, Rovira O, et al. . Circulating Irisin and Myostatin as Markers of Muscle Strength and Physical Condition in Elderly Subjects. Front Physiol (2019) 10:871. doi: 10.3389/fphys.2019.00871
    1. Pearsall RS, Davies MV, Cannell M, Li J, Widrick J, Mulivor AW, et al. . Follistatin-Based Ligand Trap ACE-083 Induces Localized Hypertrophy of Skeletal Muscle With Functional Improvement in Models of Neuromuscular Disease. Sci Rep (2019) 9(1):11392. doi: 10.1038/s41598-019-47818-w
    1. Suh J, Lee YS. Myostatin Inhibitors: Panacea or Predicament for Musculoskeletal Disorders? J Bone Metab (2020) 27(3):151–65. doi: 10.11005/jbm.2020.27.3.151
    1. Faye PA, Poumeaud F, Miressi F, Lia AS, Demiot C, Magy L, et al. . Focus on 1,25-Dihydroxyvitamin D3 in the Peripheral Nervous System. Front Neurosci (2019) 13:348. doi: 10.3389/fnins.2019.00348
    1. Abdala R, Levi L, Longobardi V, Zanchetta MB. Severe Bone Microarchitecture Deterioration in a Family With Hereditary Neuropathy: Evidence of the Key Role of the Mechanostat. Osteoporos Int (2020) 31(12):2477–80. doi: 10.1007/s00198-020-05674-9
    1. Faienza MF, Brunetti G, Grugni G, Fintini D, Convertino A, Pignataro P, et al. . The Genetic Background and Vitamin D Supplementation Can Affect Irisin Levels in Prader-Willi Syndrome. J Endocrinol Invest (2021) 44(10):2261–71. doi: 10.1007/s40618-021-01533-4
    1. Pouwels S, de Boer A, Leufkens HG, Weber WE, Cooper C, de Vries F. Risk of Fracture in Patients With Charcot-Marie-Tooth Disease. Muscle Nerve (2014) 50(6):919–24. doi: 10.1002/mus.24240
    1. Singhal V, Lawson EA, Ackerman KE, Fazeli PK, Clarke H, Lee H, et al. . Irisin Levels Are Lower in Young Amenorrheic Athletes Compared With Eumenorrheic Athletes and Non-Athletes and Are Associated With Bone Density and Strength Estimates. PloS One (2014) 9(6):e100218. doi: 10.1371/journal.pone.0100218
    1. Pignataro P, Dicarlo M, Zerlotin R, Zecca C, Dell'Abate MT, Buccoliero C, et al. . FNDC5/Irisin System in Neuroinflammation and Neurodegenerative Diseases: Update and Novel Perspective. Int J Mol Sci (2021) 22(4):1605. doi: 10.3390/ijms22041605
    1. Aydin S, Kuloglu T, Aydin S, Eren MN, Celik A, Yilmaz M, et al. . Cardiac, Skeletal Muscle and Serum Irisin Responses to With or Without Water Exercise in Young and Old Male Rats: Cardiac Muscle Produces More Irisin Than Skeletal Muscle. Peptides (2014) 52:68–73. doi: 10.1016/j.peptides.2013.11.024
    1. Wrann CD, White JP, Salogiannnis J, Laznik-Bogoslavski D, Wu J, Ma D, et al. . Exercise Induces Hippocampal BDNF Through a PGC-1α/FNDC5 Pathway. Cell Metab (2013) 18(5):649–59. doi: 10.1016/j.cmet.2013.09.008
    1. Azimi M, Gharakhanlou R, Naghdi N, Khodadadi D, Heysieattalab S. Moderate Treadmill Exercise Ameliorates Amyloid-β-Induced Learning and Memory Impairment, Possibly via Increasing AMPK Activity and Up-Regulation of the PGC-1α/FNDC5/BDNF Pathway. Peptides (2018) 102:78–88. doi: 10.1016/j.peptides.2017.12.027

Source: PubMed

Sponzoři a spolupracovníci

Zdravotní podmínky

Drogové intervence

3
Předplatit