Elena Monti

All Publications

• C-terminal agrin fragment as a biomarker of muscle wasting and weakness: a narrative review. Journal of cachexia, sarcopenia and muscle Monti, E., Sarto, F., Sartori, R., Zanchettin, G., Lofler, S., Kern, H., Narici, M. V., Zampieri, S. 2023

  Abstract

  Ageing is accompanied by an inexorable loss of muscle mass and functionality and represents a major risk factor for numerous diseases such as cancer, diabetes and cardiovascular and pulmonary diseases. This progressive loss of muscle mass and function may also result in the insurgence of a clinical syndrome termed sarcopenia, exacerbated by inactivity and disease. Sarcopenia and muscle weakness yield the risk of falls and injuries, heavily impacting on health and social costs. Thus, screening, monitoring and prevention of conditions inducing muscle wasting and weakness are essential to improve life quality in the ageing modern society. To this aim, the reliability of easily accessible and non-invasive blood-derived biomarkers is being evaluated. C-terminal agrin fragment (CAF) has been widely investigated as a neuromuscular junction (NMJ)-related biomarker of muscle dysfunction. This narrative review summarizes and critically discusses, for the first time, the studies measuring CAF concentration in young and older, healthy and diseased individuals, cross-sectionally and in response to inactivity and physical exercise, providing possible explanations behind the discrepancies observed in the literature. To identify the studies investigating CAF in the above-mentioned conditions, all the publications found in PubMed, written in English and measuring this biomarker in blood from 2013 (when CAF was firstly measured in human serum) to 2022 were included in this review. CAF increases with age and in sarcopenic individuals when compared with age-matched, non-sarcopenic peers. In addition, CAF was found to be higher than controls in other muscle wasting conditions, such as diabetes, COPD, chronic heart failure and stroke, and in pancreatic and colorectal cancer cachectic patients. As agrin is also expressed in kidney glomeruli, chronic kidney disease and transplantation were shown to have a profound impact on CAF independently from muscle wasting. CAF concentration raises following inactivity and seems to be lowered or maintained by exercise training. Finally, CAF was reported to be cross-sectionally correlated to appendicular lean mass, handgrip and gait speed; whether longitudinal changes in CAF are associated with those in muscle mass or performance following physical exercise is still controversial. CAF seems a reliable marker to assess muscle wasting in ageing and disease, also correlating with measurements of appendicular lean mass and muscle function. Future research should aim at enlarging sample size and accurately reporting the medical history of each patient, to normalize for any condition, including chronic kidney disease, that may influence the circulating concentration of this biomarker.

  View details for DOI 10.1002/jcsm.13189

  View details for PubMedID 36772862

• Effects of a 2-year exercise training on neuromuscular system health in older individuals with low muscle function JOURNAL OF CACHEXIA SARCOPENIA AND MUSCLE Monti, E., Tagliaferri, S., Zampieri, S., Sarto, F., Sirago, G., Franchi, M., Ticinesi, A., Longobucco, Y., Adorni, E., Lauretani, F., Von Haehling, S., Marzetti, E., Calvani, R., Bernabei, R., Cesari, M., Maggio, M., Narici, M. 2023

  Abstract

  Ageing is accompanied by a progressive loss of skeletal muscle mass and strength, potentially determining the insurgence of sarcopenia. Evidence suggests that motoneuron and neuromuscular junction (NMJ) degeneration contribute to sarcopenia pathogenesis. Seeking for strategies able to slow down sarcopenia insurgence and progression, we investigated whether a 2-year mixed-model training involving aerobic, strength and balance exercises would be effective for improving or preserving motoneuronal health and NMJ stability, together with muscle mass, strength and functionality in an old, sarcopenic population.Forty-five sarcopenic elderly (34 females; 11 males) with low dual-energy X-ray absorptiometry (DXA) lean mass and Short Physical Performance Battery (SPPB) score <9 were randomly assigned to either a control group [Healthy Aging Lifestyle Education (HALE), n = 21] or an intervention group [MultiComponent Intervention (MCI), n = 24]. MCI trained three times per week for 2 years with a mix of aerobic, strength and balance exercises matched with nutritional advice. Before and after the intervention, ultrasound scans of the vastus lateralis (VL), SPPB and a blood sample were obtained. VL architecture [pennation angle (PA) and fascicle length (Lf)] and cross-sectional area (CSA) were measured. As biomarkers of neuronal health and NMJ stability status, neurofilament light chain (NfL) and C-terminal agrin fragment (CAF) concentrations were measured in serum. Differences in ultrasound parameters, NfL and CAF concentration and physical performance between baseline and follow-up were tested with mixed ANOVA or Wilcoxon test. The relationship between changes in physical performance and NfL or CAF concentration was assessed through correlation analyses.At follow-up, MCI showed preserved VL architecture (PA, Lf) despite a reduced CSA (-8.4%, P < 0.001), accompanied by maintained CAF concentration and ameliorated overall SPPB performance (P = 0.007). Conversely, HALE showed 12.7% decrease in muscle CSA (P < 0.001), together with 5.1% and 5.5% reduction in PA and Lf (P < 0.001 and P = 0.001, respectively), and a 6.2% increase in CAF (P = 0.009) but improved SPPB balance score (P = 0.007). NfL concentration did not change in either group. In the population, negative correlations between changes in CAF concentration and SPPB total score were found (P = 0.047), whereas no correlation between NfL and SPPB variations was observed.The present findings suggest that our 2-year mixed aerobic, strength and balance training seemed effective for preventing the age and sarcopenia-related increases in CAF concentration, preserving NMJ stability as well as muscle structure (PA and Lf) and improving physical performance in sarcopenic older individuals.

  View details for DOI 10.1002/jcsm.13173

  View details for Web of Science ID 000919027100001

  View details for PubMedID 36708273

• Motor units alterations with muscle disuse: what is new? The Journal of physiology Sarto, F., Valli, G., Monti, E. 2022

  View details for DOI 10.1113/JP283868

  View details for PubMedID 36200458

• Effects of short-term unloading and active recovery on human motor unit properties, neuromuscular junction transmission and transcriptomic profile. The Journal of physiology Sarto, F., Stashuk, D. W., Franchi, M. V., Monti, E., Zampieri, S., Valli, G., Sirago, G., Candia, J., Hartnell, L. M., Paganini, M., McPhee, J. S., De Vito, G., Ferrucci, L., Reggiani, C., Narici, M. V. 2022

  Abstract

  KEY POINTS: We used integrative electrophysiological and molecular approaches to comprehensively investigate changes in neuromuscular integrity and function after a 10-day unilateral lower limb suspension (ULLS), followed by 21days of active recovery (AR) in young healthy men, with a particular focus on neuromuscular junction (NMJ) and motor unit potential (MUP) properties alterations. After 10-day ULLS, we found significant NMJ molecular alterations in absence of NMJ transmission stability impairment. These findings suggest that human NMJ is functionally resilient against insults and stresses induced by short-term disuse at least at relatively low contraction intensities, at which low-threshold, slow-type MUs are recruited. Intramuscular electromyography revealed that unloading caused increased MUP complexity and decreased motor unit firing rates, and these alterations could be related to the observed changes in skeletal muscle ion channel pool and initial and partial signs of fibre denervation and axonal damage. The AR period restored these neuromuscular changes.ABSTRACT: Electrophysiological alterations of the neuromuscular junction (NMJ) and motor unit potential (MUP) with unloading are poorly studied. We aimed to investigate these aspects and the underlying molecular mechanisms with short-term unloading and active recovery (AR). Eleven healthy males underwent a 10-day unilateral lower limb suspension (ULLS) period, followed by 21-day AR based on resistance exercise. Quadriceps femoris (QF) cross-sectional area (CSA) and isometric maximum voluntary contraction (MVC) were evaluated. Intramuscular electromyographic recordings were obtained during 10% and 25% MVC isometric contractions from the vastus lateralis (VL). Biomarkers of NMJ molecular instability (serum c-terminal agrin fragment, CAF), axonal damage (neurofilament light chain) and denervation status were assessed from blood samples and VL biopsies. NMJ and ion channels transcriptomic profiles were investigated by RNA-sequencing. QF CSA and MVC decreased with ULLS. Increased CAF and altered NMJ transcriptome with unloading suggested the emergence of NMJ molecular instability, which was not associated with impaired NMJ transmission stability. Instead, increased MUP complexity and decreased motor unit firing rates were found after ULLS. Downregulation of ion channel gene expression was found together with increased neurofilament light chain concentration and partial denervation. The AR period restored most of these neuromuscular alterations. In conclusion, the human NMJ is destabilized at the molecular level but shows functional resilience to a 10-day unloading period at least at relatively low contraction intensities. However, MUP properties are altered by ULLS, possibly due to alterations in ion channel dynamics and initial axonal damage and denervation. These changes are fully reversed by 21-day AR. Abstract figure legend Eleven young males took part in a 10-day unilateral lower limb suspension (ULLS) intervention. This unloading period was followed by 21days of subsequent active recovery (AR) based on resistance exercise. At baseline, after ULLS and after AR we evaluated muscle size by ultrasound and in vivo muscle function by isometric dynamometry. Motor unit potential (MUP) properties and neuromuscular junction (NMJ) transmission stability were assessed using intramuscular electromyography. Finally, vastus lateralis muscle biopsies and blood samples were collected. The ULLS intervention resulted in increased NMJ molecular instability in absence of NMJ transmission stability impairment. Changes in MUP properties were observed, including increased MUP complexity and decreased motor unit firing rates, possibly due to initial axonal damage, partial denervation and altered in ion channels dynamics. The AR period was effective in restoring these neuromuscular changes. LS0: baseline data collection; LS10: unilateral lower limb suspension day 10; AR21: active recovery day 21 This article is protected by copyright. All rights reserved.

  View details for DOI 10.1113/JP283381

  View details for PubMedID 36071599