Short reportSerum levels of C-terminal agrin fragment (CAF) are associated with sarcopenia in older hip fractured patients
Introduction
Hip fracture is the most burdensome consequence of osteoporosis. Approximately 1.6 million older adults sustain a hip fracture worldwide annually, and this figure is projected to worsen due to the ongoing demographic transition (Pioli et al., 2014). Although advancements have been made in the surgical and clinical management of hip fractured patients, mortality rates remain extremely high (over 30% at one year), with incomplete restoration of pre-fractural conditions in more than 50% of survivors (Maggi et al., 2010). These considerations call for the development of novel strategies to improve the survival and functional recovery of this vulnerable patient population.
Among the factors that may impact the clinical outcome of hip fractured elderly, the age-related loss of muscle mass and function (sarcopenia) emerges as serious candidate for interventions. Indeed, the skeletal muscle, besides its role in mobility, is also critically involved in inflammatory and immune signaling, glucose disposal, and protein synthesis. Notably, the presence of sarcopenia was identified as an independent predictor of poor clinical outcomes, including disability and mortality, in older adults admitted to acute care (Vetrano et al., 2014) or intensive care units (ICUs) (Moisey et al., 2013).
The limited availability of equipment for muscle mass estimation and difficulties with functional testing in critically ill patients have so far impeded the incorporation of sarcopenia into standard practice. Considerable research efforts have therefore been diverted toward developing and validating blood-borne biomarkers for sarcopenia which could obviate the need for imaging and performance testing (Marzetti, 2012).
The circulating C-terminal agrin fragment (CAF) has recently been proposed as a marker for muscle atrophy in both humans (Drey et al., 2013, Hettwer et al., 2013) and animal models (Bütikofer et al., 2011). Agrin is a heparan sulfate proteoglycan synthesized in motor neurons, transported along axons and released into the synaptic basal lamina of the neuromuscular junction (NMJ), where it induces the assembly of the postsynaptic apparatus, including the clustering of acetylcholine receptors, and the stabilization of presynaptic structures (Stephan et al., 2008). The proteolytic cleavage of agrin at the NMJ by neurotrypsin produces a C-terminal 22-kDa fragment (CAF), which is released into the circulation and is therefore measurable (Stephan et al., 2008). In mice, overexpression of neurotrypsin in motor neurons results in reduced agrin levels at the NMJ (Bütikofer et al., 2011). These mice are characterized by early declines in muscle mass and strength, with histopathological traits mimicking those of sarcopenia (e.g., type II fiber loss, increased heterogeneity of fiber diameter, higher frequency of centralized nuclei, fiber-type grouping, and type I to type II fiber transition) (Bütikofer et al., 2011). These findings indicate that an excessive cleavage of agrin results in NMJ fragmentation and fiber denervation, which in turn may contribute to the pathogenesis of sarcopenia.
While studies have shown that serum CAF may serve as a biomarker for sarcopenia in community-dwelling elderly (Drey et al., 2013, Hettwer et al., 2013), its validity in the presence of acute medical conditions has yet to be established. In particular, in traumatized patients, such as those sustaining a hip fracture, the muscular mechanical damage could result in extensive shedding of NMJ constituents, including CAF, into the circulation. This could theoretically offset eventual pre-existing differences linked to the presence of sarcopenia, thereby precluding the use of CAF as a muscle wasting biomarker in this patient population.
Based on these considerations, the present exploratory study was undertaken to verify if serum CAF levels were associated with sarcopenia in a cohort of older adults hospitalized for traumatic hip fracture.
Section snippets
Study sample
The study was performed between November 2012 and August 2013 among older adults admitted for hip fracture due to accidental fall to the Emergency Department (ED) of the Teaching Hospital “Agostino Gemelli”, Catholic University of the Sacred Heart (Rome, Italy). Exclusion criteria were age < 65 years, presence of peripheral edema, bone metastasis, cognitive impairment (Cognitive Performance Scale, CPS < 3), presence of pacemaker or implantable cardioverter defibrillator, and unwillingness to take
Results
A total of 42 hip fractured patients were enrolled for the study. The main characteristics of the study sample are shown in Table 1. Women were predominant (76.2%), which is coherent with epidemiological data showing a higher incidence of hip fracture in the female gender (Cauley et al., 2014). Sarcopenia was identified in 7 patients (16.7%), with a higher prevalence in men than women. Relative to non-sarcopenic patients, subjects with sarcopenia showed poorer pre-fractural physical function,
Discussion
Over the last decades, considerable efforts have been directed toward the development of interventions aimed at reducing the incidence of hip fractures and improving the health outcomes once the fracture has occurred (Pioli et al., 2014). Yet, the prognosis of older adults with hip fractured remains extremely poor (Maggi et al., 2010). Indeed, a shift of paradigm is necessary to optimize the management of such a vulnerable patient population. Accordingly, hip fracture should no longer be viewed
Conflict of interest
None of the authors has any conflict of interest to disclose.
Acknowledgments
This study was supported by the “Centro Studi Achille e Linda Lorenzon” (E.M., L.M., R.C.), a grant from the Italian Ministry of Education, Universities and Research (MIUR — linea D3.2 2013; A.M.M., E.M., F.L.), and the Innovative Medicines Initiative Joint Undertaking (IMI-JU 115621; E.M., F.L., R.C.).
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These two authors contributed equally to this work.