Association between the 110‐kDa C‐terminal agrin fragment and skeletal muscle decline among community‐dwelling older women

BACKGROUND C-terminal agrin fragment (CAF) is a biomarker for neuromuscular junction degradation. This study aimed to investigate whether 110-kDa CAF (CAF110) was associated with the presence and incidence of low muscle mass and strength. METHODS This cross-sectional retrospective cohort study comprised women aged ≥65 years. We measured muscle mass using a dual-energy X-ray absorptiometry scanner, hand-grip strength, and blood sampling between 2011 and 2012. A follow-up study with the same measurements was conducted between 2015 and 2017. Low muscle mass and strength were defined as an appendicular skeletal muscle mass index <5.4 kg/m2 and hand-grip strength <18 kg, respectively. The CAF110 level was measured using enzyme-linked immunosorbent assay kits. RESULTS In total, 515 women (74.3 ± 6.3 years) were included in this cross-sectional analysis. Of these, 101 (19.6%) and 128 (24.9%) women presented with low muscle mass and strength, respectively. For low muscle mass, the odds ratios (ORs) of the middle and highest CAF110 tertile groups, compared with the lowest group, were 1.93 (95% confidence interval: 1.09-3.43; P = 0.024) and 2.15 (1.22-3.80; P = 0.008), respectively. After adjusting for age, the ORs remained significant: 1.98 (1.11-3.52; P = 0.020) and 2.27 (1.28-4.03; P = 0.005), respectively. Low muscle strength ORs of all the CAF110 tertile groups were not significant. In the longitudinal analysis, 292 and 289 women were assessed for incidents of low muscle mass and strength, respectively. Of those, 34 (11.6%) and 20 (6.9%) women exhibited low muscle mass and strength, respectively. For incident low muscle mass, the crude OR of the CAF110 ≥ the median value group was marginally higher than that of the CAF110 < median value group (median [interquartile range]: 1.98 [0.94-4.17] (P = 0.072). After adjusting for age and baseline muscle mass, the OR was 2.22 [0.97-5.06] (P = 0.058). All low muscle strength ORs of the median categories of CAF110 were not significant. CONCLUSIONS CAF110 was not associated with low muscle strength. However, CAF110 may be a potential marker for the incidence of low muscle mass.

[1]  J. Conroy,et al.  Plasma C-Terminal Agrin Fragment as an Early Biomarker for Sarcopenia: Results From the GenoFit Study , 2021, The journals of gerontology. Series A, Biological sciences and medical sciences.

[2]  M. Narici,et al.  Neuromuscular junction instability and altered intracellular calcium handling as early determinants of force loss during unloading in humans , 2021, The Journal of physiology.

[3]  Yan Zhang,et al.  Sarcopenia in heart failure: a systematic review and meta‐analysis , 2021, ESC heart failure.

[4]  M. Narici,et al.  Neuromuscular Junction Aging: A Role for Biomarkers and Exercise. , 2020, The journals of gerontology. Series A, Biological sciences and medical sciences.

[5]  D. Goulis,et al.  Type 2 Diabetes Mellitus is Associated with Increased Risk of Sarcopenia: A Systematic Review and Meta-analysis , 2020, Calcified Tissue International.

[6]  L. Peng,et al.  Asian Working Group for Sarcopenia: 2019 Consensus Update on Sarcopenia Diagnosis and Treatment. , 2020, Journal of the American Medical Directors Association.

[7]  A. Cruz-Jentoft,et al.  Biomarkers of sarcopenia in very old patients with hip fracture , 2020, Journal of cachexia, sarcopenia and muscle.

[8]  D. Jones,et al.  Five-year longitudinal changes in thigh muscle mass of septuagenarian men and women assessed with DXA and MRI , 2019, Aging Clinical and Experimental Research.

[9]  René Rizzoli,et al.  Sarcopenia: revised European consensus on definition and diagnosis , 2018, Age and ageing.

[10]  Yuan-Fang Li,et al.  The Reference Intervals for Serum C‐Terminal Agrin Fragment in Healthy Individuals and as a Biomarker for Renal Function in Kidney Transplant Recipients , 2017, Journal of clinical laboratory analysis.

[11]  P. Abete,et al.  Biomarkers in sarcopenia: A multifactorial approach , 2016, Experimental Gerontology.

[12]  T. Malmstrom,et al.  Frailty and Sarcopenia as Predictors of Adverse Health Outcomes in Persons With Diabetes Mellitus. , 2016, Journal of the American Medical Directors Association.

[13]  G. Onder,et al.  Serum levels of C-terminal agrin fragment (CAF) are associated with sarcopenia in older multimorbid community-dwellers: Results from the ilSIRENTE study , 2016, Experimental Gerontology.

[14]  F. Raymond,et al.  A robust neuromuscular system protects rat and human skeletal muscle from sarcopenia , 2016, Aging.

[15]  C. Wagner,et al.  C-Terminal Fragment of Agrin (CAF): A Novel Marker for Progression of Kidney Disease in Type 2 Diabetics , 2015, PloS one.

[16]  S. Anker,et al.  Detection of muscle wasting in patients with chronic heart failure using C‐terminal agrin fragment: results from the Studies Investigating Co‐morbidities Aggravating Heart Failure (SICA‐HF) , 2015, European journal of heart failure.

[17]  M. Iki,et al.  Cohort Profile Cohort Profile : The Japanese Population-based Osteoporosis ( JPOS ) Cohort Study , 2015 .

[18]  D. Jones,et al.  Comparison of MRI and DXA to measure muscle size and age-related atrophy in thigh muscles. , 2013, Journal of musculoskeletal & neuronal interactions.

[19]  R. Nagatomi,et al.  An inverted J-shaped association of serum uric acid with muscle strength among Japanese adult men: a cross-sectional study , 2013, BMC Musculoskeletal Disorders.

[20]  S. Anker,et al.  C-terminal agrin-fragment as a novel diagnostic marker for muscle wasting in patients with chronic heart failure: results from the studies investigating co-morbidities aggravating heart failure , 2013 .

[21]  M. Bolliger,et al.  Zymogen activation of neurotrypsin and neurotrypsin-dependent agrin cleavage on the cell surface are enhanced by glycosaminoglycans. , 2013, The Biochemical journal.

[22]  P. Kwan Sarcopenia, a Neurogenic Syndrome? , 2013, Journal of aging research.

[23]  W. Uter,et al.  C-terminal Agrin Fragment as a potential marker for sarcopenia caused by degeneration of the neuromuscular junction , 2013, Experimental Gerontology.

[24]  P. Dahinden,et al.  Elevated levels of a C-terminal agrin fragment identifies a new subset of sarcopenia patients , 2013, Experimental Gerontology.

[25]  M. Bolliger,et al.  Destabilization of the neuromuscular junction by proteolytic cleavage of agrin results in precocious sarcopenia , 2011, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[26]  M. Francolini,et al.  Specific proteolytic cleavage of agrin regulates maturation of the neuromuscular junction , 2010, Journal of Cell Science.

[27]  K. Shigemoto,et al.  Muscle weakness and neuromuscular junctions in aging and disease , 2010, Geriatrics & gerontology international.

[28]  M. Deschenes,et al.  Remodeling of the neuromuscular junction precedes sarcopenia related alterations in myofibers , 2010, Experimental Gerontology.

[29]  M. Kjaer,et al.  Role of the nervous system in sarcopenia and muscle atrophy with aging: strength training as a countermeasure , 2010, Scandinavian journal of medicine & science in sports.

[30]  Yasuhiko Tomino,et al.  Revised equations for estimated GFR from serum creatinine in Japan. , 2009, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[31]  P. Sonderegger,et al.  Neurotrypsin cleaves agrin locally at the synapse , 2008, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[32]  Kazutoshi Nakamura,et al.  Development of a simple food frequency questionnaire to estimate intakes of calcium and other nutrients for the prevention and management of osteoporosis. , 2008, Journal of nutritional science and vitaminology.

[33]  T. Lømo,et al.  Neural agrin controls acetylcholine receptor stability in skeletal muscle fibers , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[34]  M. Ruegg,et al.  Acetylcholine receptor-aggregating activity of agrin isoforms and mapping of the active site , 1995, The Journal of cell biology.

[35]  Y. Fujita,et al.  Muscle strength is associated with bone health independently of muscle mass in postmenopausal women: the Japanese population-based osteoporosis study , 2017, Journal of Bone and Mineral Metabolism.

[36]  M A Laskey,et al.  Dual-energy X-ray absorptiometry and body composition. , 1996, Nutrition.

[37]  Human Experimentation: Code of Ethics of the World Medical Association (Declaration of Helsinki). , 1964, Canadian Medical Association journal.