Leader: Maria Grano (UNIBA); Other collaborator(s):
We plan to investigate the mechanisms underlying the age-related diseases osteoporosis and sarcopenia in relevant animal models and to identify and validate new therapeutic targets that can be used to promote anabolic responses in bone and skeletal muscle as anti-aging agents.
Brief description of the activities and of the intermediate results
- Two oral contributions selected for the Age-It General Meeting. Ca' Foscari Venice, May 20-22, 2024:
- Irisin enhances memory and spatial learning by modulating neuroplasticity factors in the brain of aged mice
- Prolonged treatment with irisin counteracts bone loss and muscle fiber degeneration in aged mice.
- We completed the treatment of 12-month-old C57BL6 mice injected subcutaneously with vehicle or irisin for 8 months.
- To evaluate memory and spatial learning, mice were submitted to the behavioral paradigm, Morris water maze. The results revealed that irisin administration was effective in improving the mouse ability to learn and remember the location of the escape platform.
- To understand the molecular mechanisms underlying the effect of irisin on memory and spatial learning, we evaluated gene expression of factors involved in neuroplastic processing and control of synaptogenesis, in the hippocampus and prefrontal cortex.
- To evaluate the effect of irisin on the skeleton, an ex-vivo analysis of the femurs was performed by microCT, measuring morphological indices of the metaphyseal regions of the femurs. Femurs of mice treated with irisin showed an increase in cortical bone mineral density, bone surface, trabecular bone volume fraction and number of trabeculae compared with vehicle-mice. The treatment with irisin also increased fractal dimension and reduced the degree of anisotropy, thereby indicating an improved microstructural organization of trabecular bone.
- We also evaluated the effect of irisin on skeletal muscle. Results showed that irisin preserved the morphological organization of muscle fibers in the quadriceps compared with vehicle mice.
Main policy, industrial and scientific implications
Our results revealed that prolonged systemic treatment with irisin in aged mice improved memory and spatial cognitive abilities, mimicking exercise-induced effects, by increasing the expression of neuroplasticity factors and activity of the FNDC5/irisin system mainly in the hippocampus. Moreover, our results demonstrated that irisin is effective in increasing bone mass and inhibiting muscle fiber degeneration. These findings provide the first evidence for the possibility of using the therapeutic treatment with irisin for age-related cognitive and musculoskeletal decline.
To evaluate the potential role of irisin as a biomarker of osteosarcopenia and neurodegeneration in age-related diseases, we collected cerebrospinal fluid (CSF) and plasma samples from patients with diagnosis of Alzheimer dementia (AD, n=82), mild cognitive impairment (MCI, n=44), and subjective memory complaint (SMC, n=20).
We quantified irisin levels by ELISA assays and we correlated these results with clinical and fluid AD biomarkers. We observed that CSF irisin was reduced in AD patients, with lower levels in females. Moreover, CSF irisin correlated positively with Aβ42 in both female and male patients, and negatively with CDR-SOB only in females. A negative trend was also observed between CSF irisin and t-tau levels in all patients and in the female subgroup.
In parallel, we conducted other studies in mouse model of depression, osteoporosis, and bone disease associated to multiple myeloma.
DISSEMINATION
Two oral contributions selected for the Age-It General Meeting. Ca' Foscari Venice, May 20-22, 2024:
- Irisin enhances memory and spatial learning by modulating neuroplasticity factors in the brain of aged mice
- Prolonged treatment with irisin counteracts bone loss and muscle fiber degeneration in aged mice.
Two poster contributions selected for International Meetings:
- Irisin levels in cerebrospinal fluid correlate with biomarkers and clinical dementia scores in Alzheimer’s disease (FENS Forum 2024, 25-29 June 2024, Vienna, Austria).
- Irisin levels in cerebrospinal fluid correlate with biomarkers and clinical dementia scores in Alzheimer’s disease (37th ECNP, 21-24 September 2024, Milano, Italy).
To evaluate the potential role of irisin as a biomarker of neurodegeneration in age-related diseases, we measured plasma irisin levels in patients with Parkinson’s disease (PD, n=82) and healthy controls (HD, n=89) matched for age and sex, and we correlated the results of this analysis with PD clinical variables. We observed that PD patients had significantly lower plasma irisin levels compared to HC. Moreover, a significant correlation between memory functions and plasma irisin levels was observed in PD patients. The results of this study have been submitted to the Journal “npj Parkinson's Disease” for publication. In parallel, we conducted other studies in a mouse model of cardiac hypertrophy and fibrosis, two age-related changes that may occur in the ageing heart.
Main policy, industrial and scientific implications
Our results in PD patients suggest that plasma irisin may reflect disease-related processes in PD. Moreover, we demonstrated that treatment with systemic irisin prevents cardiac hypertrophy and fibrosis in a mouse model of cardiac hypertrophy.
- Dicarlo M, Pignataro P, Zerlotin R, Suriano C, Zecca C, Dell'Abate MT, Storlino G, Oranger A, Sanesi L, Mori G, Grano M, Colaianni G, Colucci S. Short-Term Irisin Treatment Enhanced Neurotrophin Expression Differently in the Hippocampus and the Prefrontal Cortex of Young Mice. Int J Mol Sci. 2023 May 23;24(11):9111.
- Storlino G, Dicarlo M, Zerlotin R, Pignataro P, Sanesi L, Suriano C, Oranger A, Mori G, Passeri G, Colucci S, Grano M, Colaianni G. Irisin Protects against Loss of Trabecular Bone Mass and Strength in Adult Ovariectomized Mice by Stimulating Osteoblast Activity. Int J Mol Sci. 2023 Jun 8;24(12):9896.
- Dicarlo M, Pignataro P, Zecca C, Dell'Abate MT, Urso D, Gnoni V, Giugno A, Borlizzi F, Zerlotin R, Oranger A, Colaianni G, Colucci S, Logroscino G, Grano M. Irisin Levels in Cerebrospinal Fluid Correlate with Biomarkers and Clinical Dementia Scores in Alzheimer Disease. Ann Neurol. 2024 Jul;96(1):61-73.
- Zerlotin R, Oranger A, Pignataro P, Dicarlo M, Sanesi L, Suriano C, Storlino G, Rizzi R, Mestice A, Di Gioia S, Mori G, Grano M, Colaianni G, Colucci S. Irisin prevents trabecular bone damage and tumor invasion in a mouse model of multiple myeloma. JBMR Plus. 2024 May 23;8(7):ziae066.
- Suriano C, Zerlotin R, Pignataro P, Dicarlo M, Oranger A, Zanfino L, De Santis A, Tunnera S, Colucci S, Grano M, Colaianni G. Irisin Treatment Prevents Isoproterenol-Induced Cardiac Fibrosis in Mice. Discov Med. 2024 Nov;36(190):2202-2213. doi: 10.24976/Discov.Med.202436190.202.