Biology subjects

Moreno-Martinez, L.

Publications and source records attributed to Moreno-Martinez, L..

5 recordsLinked to original sources

bioRxiv2026

Loss of TDP-43 drives premature aging and impairs skeletal muscle stem cell pool restoration

TAR DNA-binding protein 43 (TDP-43) dysfunction is a hallmark of amyotrophic lateral sclerosis (ALS) and related disorders, yet its role in skeletal muscle stem cells, the satellite cells (SC), remains incompletely understood. Here, we investigated ALS-associated gain- and loss-of-function TDP-43 mutations together with inducible SC-specific TDP-43 deletion. While TDP-43Q331K and heterozygous TDP-43F210I mice displayed normal muscle homeostasis, SC abundance, and regenerative capacity, complete TDP-43 loss caused a marked reduction of the SC pool, particularly in females, and shifted SCs from a CD34high stem-like state toward a CD34low primed population. TDP-43-deficient SCs failed to clonally expand, proliferate, and differentiate, resulting in severe regenerative failure following muscle injury. Notably, the SC pool failed to recover after injury and was nearly depleted 30 days post-injury, accompanied by muscle loss, fibrosis and fat infiltration. Transcriptomic analyses revealed activation of stress and aging-associated programs in uninjured TDP-43-deficient SCs, indicating the premature acquisition of an aging-like state. Consistently, chronological aging further exacerbated SC depletion, establishing TDP-43 as a critical regulator of SC stemness, regeneration, and resistance to age-related decline.

cell biology↗

bioRxiv2026

Muscle spatial lipidomics identifies early ALS signatures in presymptomatic SOD1G93A mice

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease whose diagnosis often remains delayed. Skeletal muscle is increasingly recognized as an early contributor to ALS pathology. Using lipid imaging mass spectrometry (LIMS) in Tibialis anterior muscle from hSOD1G93A mice across disease stages, we identified fiber-type-specific and sex-dependent lipid remodeling. Lipid alterations were detected at the presymptomatic stage, preceding motor neuron loss and clinical symptoms. LIMS distinguished fast-twitch oxidative-glycolytic (type IIA) and glycolytic (type IIB/IIX) fibers and revealed their differential vulnerability to disease. Presymptomatic mutant muscles showed loss of physiological lipid signatures alongside disease-specific lipid changes. Although lipid profiles differed between sexes, ALS-associated alterations enabled accurate discrimination of mutant mice before symptom onset. Importantly, similar disease-related lipid changes were detected in serum, enabling accurate classification of presymptomatic animals. These findings establish lipid remodeling as an early ALS event and highlight novel biomarkers with potential for diagnosis and disease monitoring.

neuroscience↗

bioRxiv2026

Comprehensive characterization of skeletal muscle remodeling in hSOD1G93A mice reveals limited functional impact of systemic FOXO1 inhibition

BackgroundAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by progressive motor neuron (MN) loss, muscle atrophy and paralysis. Although traditionally considered a MN-specific disease, accumulating evidence supports a crucial contribution of skeletal muscle pathology to disease onset and progression. Except for specific mutations, to date there is no effective treatment for ALS. FOXO transcription factors regulate programs of atrophy, metabolism and stress response in skeletal muscle, and their inhibition has shown beneficial effects in cellular and Drosophila models of ALS. MethodsIn this study, we investigated whether pharmacological FOXO inhibition (iFOXO) could modify disease progression and muscle pathology in female hSOD1G93A mice. Mice received daily oral administration of iFOXO starting at presymptomatic (P50; n=5 per group) or symptomatic (P90; n=9 mice per group) stages until end-stage. Body weight was monitored longitudinally, and motor performance was evaluated using grip strength and hanging-wire tests. Tibialis anterior and soleus muscles, representing fast- and slow-twitch muscles respectively, were analyzed by histology and immunofluorescence to assess fiber atrophy, fibrosis, lipid accumulation, satellite cell pool and fiber type composition. Quadriceps muscles (n=3 per group) were used for RNA-seq analysis. ResultsWhile histological analyses revealed severe fiber atrophy and increased fibrosis in hSOD1G93A mice, satellite cell numbers were preserved or mildly increased in a muscle and treatment onset dependent manner. iFOXO treatment did not improve motor performance, survival or attenuate muscle atrophy. Transcriptomic profiling indicated that genotype was the predominant driver of gene expression changes, while iFOXO produced only subtle, treatment onset dependent effects on pathways related to oxidative stress responses, mitochondrial function and adaptive metabolism. ConclusionOverall, FOXO inhibition alone showed limited therapeutic benefit in the hSOD1G93A ALS mouse model. These findings highlight the dominant influence of ALS driven molecular alterations over pharmacological modulation and emphasize the need for combinatorial therapeutic strategies targeting multiple disease mechanisms, including those preserving nerve health.

neuroscience↗

bioRxiv2024

Novel FKBP12 ligand promotes functional improvement in SOD1-G93A ALS mice

Amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease with limited treatment options. ALS pathogenesis involves intricate processes within motor neurons (MNs), characterized by dysregulated Ca2+ influx and buffering in early ALS-affected MNs. This study proposes the modulation of ryanodine receptors (RyRs), key mediators of intracellular Ca2+, as a therapeutic target. A novel class of novel FKBP12 ligands that show activity as cytosolic calcium modulators through stabilizing RyR channel activity, were tested in the SOD1G93A mouse model of ALS. Different outcomes were used to assess treatment efficacy including electrophysiology, histopathology, neuromuscular function, and survival. Among the novel FKBP12 ligands, MP-010 was chosen for its central nervous system availability. Chronic administration of MP-010 to SOD1G93A mice produced a dose-dependent preservation of motor nerve conduction, with the 61 mg/kg dose significantly delaying the onset of motor impairment. This was accompanied by improved motor coordination, increased innervated endplates, and significant preservation of MNs in the spinal cord of treated mice. Notably, MP-010 treatment significantly extended lifespan by an average of 10 days compared to vehicle. In conclusion, FKBP12 ligands, particularly MP-010, exhibit promising neuroprotective effects in ALS, highlighting their potential as novel therapeutic agents. Further investigations into the molecular mechanisms and clinical translatability of these compounds are needed for their application in ALS treatment.

neuroscience↗

bioRxiv2023

Injectable borax-loaded alginate hydrogels reduce muscle atrophy, inflammation and generate neuroprotection in the SOD1G93A mouse model of ALS

Amyotrophic Lateral Sclerosis (ALS) is the most frequent and fatal condition that causes motor neuron loss and skeletal muscle paralysis. Although ALS is associated with mutations in over 40 genes, its etiology remains largely elusive without a cure or effective treatment. Historically considered the prototype of motor neuron diseases, ALS is defined today as a multisystem disorder that presents several changes in non-neuronal cell types, such as pathological changes in muscle occurring before disease onset and independent from motor neuron degeneration (dying back hypothesis). We base on the hypothesis that skeletal muscle may have an active contribution to disease pathology and thus we consider skeletal muscle tissue as a therapeutic target for ALS. In previous works, we have demonstrated that boron transporter NaBC1 (encoded by the SLC4A11 gene), after activation co-localizes with integrins and growth factor receptors producing a functional cluster that synergistically enhances crosstalk mechanisms accelerating muscle repair. In this work, we aimed to study the effects of borax (B) in a SOD1 mouse model of ALS targeting muscle. We have engineered and characterized injectable alginate-based hydrogels with controlled local borax release to effectively activate muscle NaBC1 in vivo. Treated mice presented improved motor function and extended survival correlated with the activation of essential muscle metabolic pathways, resulting in an enhanced muscle repair response and reduced muscle atrophy and inflammation. Interestingly, the activation of muscle repair mechanisms at the local level produced retrograde neuroprotection by motor neuron preservation and reduction in neuroinflammation. Altogether, this work presents evidence supporting the involvement of muscle tissue in ALS pathology, reinforcing skeletal muscle as a primary target to develop new therapies for ALS. We propose a novel strategy based on NaBC1 activation for ALS muscle regeneration. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=139 SRC="FIGDIR/small/567052v2_ufig1.gif" ALT="Figure 1"> View larger version (50K): org.highwire.dtl.DTLVardef@16ba3e7org.highwire.dtl.DTLVardef@1d5c8c3org.highwire.dtl.DTLVardef@6f8775org.highwire.dtl.DTLVardef@2623fc_HPS_FORMAT_FIGEXP M_FIG C_FIG

neuroscience↗