Leader: Marco Narici (UNIPD); Other collaborator(s):
We plan to investigate how physical activity affects the trajectories of neuromuscular aging. Individuals aged 25-80 + years will be studied, stratified according to the level of physical activity (number of daily steps) and sarcopenic profile (according to the 2021 EWGSOP2 sarcopenia definition) . Biomarkers will be evaluated for: 1) stability of the neuromuscular junction, NMJ (c-terminal agrin fragment, serum), 2) axonal integrity (neurofilament light chain, serum), 3) denervation in muscle micro-samples (25mg): neural cell adhesion molecule (NCAM), voltage-gated sodium channel (NAV1.5), 4) expression of genes involved in NMJ integrity through RNA sequencing, 5) NMJ transmission efficiency ( by intramuscular EMG): Jiggle and Jitter, number and size of motor units, frequency of motor unit discharge and recruitment threshold, 6) dynamic balance, 7) muscle strength (handgrip and quadriceps) and walking speed, 8) muscle mass and architecture through DEXA and ultrasound.
Brief description of the activities and of the intermediate results: We have successfully recruited 180 male and female participants aged 25-91 who undewent medical screening following the exclusion criteria of the sudy. Those admitted to the study underwent testing for sarcopenia (according tho the EWGSOP2 guidelines), for physical activity level based on 7-day accelerometry and for cognitive capacity using the Montreal Cognitive Assessment (MoCA). Each individual, following informed consent, underwent the following tests: 1) muscle ultrasound for muscle size determination, 2) dynamic balance on a basculating platform, 3) voluntary muscle activation capacity, 4) intramuscular EMG (iEMG) and high -density EMG (HD-EMG), 5) venous blood sample, 6) vastus lateralis muscle biopsy. Blood samples have been separated into plasma and serum aliquots and stored at -80 for later analysis. Muscle biopsy samples have been divided into four portions, one for biochemistry, one for NMJ morphology, one for histochemistry (in OCT) and one for spatial transcriptomics. Samples have been stored at -80 for later analysis.
Brief description of the activities and of the intermediate results: We have successfully recruited 180 male and female participants aged 25-91 years who undewent medical screening following the exclusion criteria of the sudy. Those admitted to the study underwent testing for sarcopenia (according tho the EWGSOP2 guidelines), for physical activity level based on 7-day accelerometry and for cognitive capacity using the Montreal Cognitive Assessment (MoCA). Each individual, following informed consent, underwent the following tests: 1) muscle ultrasound for muscle size determination, 2) dynamic balance on a basculating platform, 3) voluntary muscle activation capacity, 4) intramuscular EMG (iEMG) and high -density EMG (HD-EMG) have been performed for the study of neuromuscular junction efficiency and motor unit recruitment properties according to patients' age 5) venous blood sample, 6) vastus lateralis muscle biopsy. Blood samples have been separated into plasma and serum aliquots and stored at -80 for later analysis. Muscle biopsy samples have been divided into four portions, one for biochemistry, one for NMJ morphology, one for histochemistry (in OCT) and one for spatial transcriptomics. Samples have been stored at -80 for later analysis.
Brief description of the activities and of the intermediate results: We have successfully recruited 180 male and female participants aged 25-91 years who undewent medical screening following the exclusion criteria of the sudy. Those admitted to the study underwent testing for sarcopenia (according tho the EWGSOP2 guidelines), for physical activity level based on 7-day accelerometry and for cognitive capacity using the Montreal Cognitive Assessment (MoCA). Each individual, following informed consent, underwent the following tests: 1) muscle ultrasound for muscle size determination, 2) dynamic balance on a basculating platform, 3) voluntary muscle activation capacity, 4) intramuscular EMG (iEMG) and high -density EMG (HD-EMG) have been performed for the study of neuromuscular junction efficiency and motor unit recruitment properties according to patients' age 5) venous blood sample, 6) vastus lateralis muscle biopsy, 7) measurements of strength (handgrip), body composition (DXA) and functional performance to assess sarcopenia and stratify enrolled population accordingly, 8) assess physical activity via accelerometers. Blood samples have been separated into plasma and serum aliquots and stored at -80 for later analysis. Muscle biopsy samples have been divided into four portions, one for biochemistry, one for NMJ morphology, one for histochemistry (in OCT) and one for spatial transcriptomics. Samples have been stored at -80 for later analysis.
Brief description of the activities and of the intermediate results: During this reporting period, data analysis of the neuromuscular and functional assessments was completed for participants across the adult lifespan. Results confirmed an age-related decline in neuromuscular function, with reductions in muscle strength (handgrip and quadriceps MVC), rate of torque development, and functional performance (gait speed, chair-to-stand, balance). Voluntary activation did not differ across age groups, suggesting preserved maximal central drive. Physical activity was positively associated with functional capacity. Higher daily step counts correlated with better mobility and performance, while more continuous activity patterns were linked to greater muscle strength. At the motor unit level, ageing was associated with reduced discharge rates and increased neuromuscular junction instability, as indicated by higher Jitter and Jiggle. More active older individuals showed signs of improved motor unit remodelling, with larger and less complex motor unit potentials. Processing of biological samples was completed, and initial biomarker analyses were initiated.
Brief description of the activities and of the intermediate results: During this reporting period, integrated analyses of neuromuscular, molecular, and neurophysiological data were completed, including the evaluation of a cohort of endurance-trained older adults. Biomarker analyses showed increased C-terminal agrin fragment (CAF) levels in very old individuals, indicating greater neuromuscular junction instability, with no clear modulation by habitual physical activity. Endurance-trained individuals demonstrated superior neuromuscular performance and functional capacity compared to untrained peers. These differences were not explained by motor unit properties, suggesting predominant central adaptations. Resting-state EEG analyses revealed more efficient brain network organization in trained individuals, with reduced age-related connectivity patterns (HAROLD and PASA effects) and improved sensorimotor integration. Cognitive performance was also enhanced. No differences were observed in BDNF and VEGF levels, while lower kynurenine-related metabolites were detected in trained individuals, suggesting long-term metabolic adaptations.
Overall, findings indicate that physical activity supports neuromuscular ageing through both peripheral and central mechanisms.
Scientific papers:
- E. Motanova, M. Pirazzini, S. Negro, O. Rossetto, M. Narici. Impact of ageing and disuse on neuromuscular junction and mitochondrial function and morphology: current evidence and controversies. Ageing Res Rev 102:102586, 2024
- F. Sarto, M.V. Franchi, J.S. McPhee, D.W. Stashuk, M. Paganini, E. Monti, M. Rossi, G. Sirago, S. Zampieri, E.S. Motanova, G. Valli, T. Moro, A. Paoli, R. Bottinelli, M.A. Pellegrino, G. De Vito, H.M. Blau, M.V. Narici. Neuromuscular impairment at different stages of human sarcopenia. J Cachexia Sarcopenia Muscle 15(5):1797-1810, 2024