Amyotrophic Lateral Sclerosis (ALS) is considered the prototype of motor neuron disease, characterized by motor neuron loss and muscle waste. A well-established pathogenic hallmark of ALS is mitochondrial failure, leading to bioenergetic deficits. So far, pharmacological interventions for the disease have proven ineffective. Trimetazidine (TMZ) is described as a metabolic modulator acting on different cellular pathways. Its efficacy in enhancing muscular and cardiovascular performance has been widely described, although its molecular target remains elusive. We addressed the molecular mechanisms underlying TMZ action on neuronal experimental paradigms. To this aim, we treated murine SOD1^G93A-model-derived primary cultures of cortical and spinal enriched motor neurons, as well as a murine motor-neuron-like cell line overexpressing SOD1^G93A, with TMZ. We first characterized the bioenergetic profile of the cell cultures, demonstrating significant mitochondrial dysfunction that is reversed by acute TMZ treatments. We then investigated the effect of TMZ in promoting autophagy processes and its impact on mitochondrial morphology. Finally, we demonstrated the effectiveness of TMZ in terms of the mitochondrial functionality of ALS-rpatient-derived peripheral blood mononuclear cells (PBMCs). In summary, our results emphasize the concept that targeting mitochondrial dysfunction may represent an effective therapeutic strategy for ALS. The findings demonstrate that TMZ enhances mitochondrial performance in motor neuron cells by activating autophagy processes, particularly mitophagy. Although further investigations are needed to elucidate the precise molecular pathways involved, these results hold critical implications for the development of more effective and specific derivatives of TMZ for ALS treatment.

Neurodegenerative diseases are distinguished by synaptic dysfunction and chronic neuroinflammation, which accelerate neuronal loss and impair network resilience. Synaptic plasticity, that is, the ability to adapt to changes, is progressively lost. This ability is part of hormesis, an adaptive biphasic response, nowadays acknowledged as a promising tool in chronic degenerative diseases, since it offers a framework for personalized interventions. Growing evidence supports exercise as a powerful approach for managing neurodegenerative disorders, due to its capacity to enhance neuroplasticity through the direct targeting of the biomolecular processes involved. Indeed, regular exercise can drive many molecular mediators and signals toward neuroplasticity improvement, potentially slowing neurodegeneration. This narrative review focuses on exercise as a promising therapeutic approach in neurodegenerative diseases, based on its ability to shape synaptic plasticity at the molecular level. Some biomediators involved in synaptic plasticity function/dysfunction and neuroinflammation/neurodegeneration are addressed as therapeutic targets of exercise, and different exercise regimens are discussed as specific therapeutic interventions to contain the burden of some neurodegenerative conditions. Some clinical trials including exercise in the treatment of neurodegenerative diseases are summarized. Since no definitive disease-modifying cure exists for these illnesses, exercise’s ability to shape synaptic plasticity emerges as a highly attractive therapeutic approach.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons. The contribution of peripheral organs remains incompletely understood. We focused our attention on brown adipose tissue (BAT) and its secreted extracellular vesicles (EVs) given their role in regulating systemic energy balance. In this study, we employed a multi-omics approach, including RNA sequencing (GEO identifier GSE273052) and proteomics (ProteomeXchange identifier PXD054147), to investigate the alterations in BAT and its EVs in the SOD1-G93A mouse model of ALS. Our results revealed consistent changes in the proteomic and transcriptomic profiles of BAT from SOD1-G93A mice, highlighting alterations such as mitochondrial dysfunction and impaired differentiation capacity. Specifically, primary brown adipocytes (PBAs) from SOD1-G93A mice exhibited differentiation impairment, respiratory defects, and alterations in mitochondrial dynamics. Furthermore, the BAT-derived EVs from SOD1-G93A mice displayed distinct changes in size distribution and cargo content. In parallel, such EVs negatively impacted the differentiation and homeostasis of C2C12 murine myoblasts, as well as induced atrophy in C2C12-derived myotubes. These findings suggest that BAT undergoes pathological perturbations in ALS mouse model and could impact on skeletal muscle homeostasis through the secretion of dysfunctional EVs.

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disease characterized by the selective loss of motor neurons. While the contribution of peripheral organs remains incompletely understood, recent evidence suggests that brown adipose tissue (BAT) and its secreted extracellular vesicles (EVs) could play a role in diseased context as ALS. In this study, we employed a multi-omics approach, including RNA sequencing (GEO identifier GSE273052) and proteomics (ProteomeXchange identifier PXD054147), to investigate the alterations in BAT and its EVs in the SOD1-G93A mouse model of ALS. Our results revealed significant changes in the proteomic and transcriptomic profiles of BAT from SOD1-G93A mice, highlighting ALS-related features such as mitochondrial dysfunction and impaired differentiation capacity. Specifically, primary brown adipocytes (PBAs) from SOD1-G93A mice exhibited differentiation impairment, respiratory defects, and alterations in mitochondrial dynamics. Furthermore, the BAT-derived EVs from SOD1-G93A mice displayed distinct changes in size distribution and cargo content, which negatively impacted the differentiation and homeostasis of C2C12 murine myoblasts, as well as induced atrophy in C2C12-derived myotubes. These findings suggest that BAT undergoes pathological perturbations in ALS, contributing to skeletal muscle degeneration through the secretion of dysfunctional EVs. This study provides novel insights into the role of BAT in ALS pathogenesis and highlights potential therapeutic targets for mitigating muscle wasting in ALS patients.