Rodriguez-Romano, A. | Search bioRxiv

bioRxiv2025

NaBC1 Acts as a Mechanosensitive Co-regulator of Fibronectin-binding Integrins Adhesion and Myoblast Polarization

Cell-matrix interactions are central to the regulation of cell mechanics, polarity, and signal transduction. In this study, we investigate the contribution of the borate transporter NaBC1 to myoblast adhesion dynamics and mechanotransductive responses. Using C2C12 myoblasts cultured on fibronectin-coated substrates, we show that NaBC1 activation rapidly reinforces cell-substrate attachment, leading to accelerated spreading and the establishment of polarized cell morphologies. These changes are associated with the assembly of enlarged focal adhesions and a marked slowdown of actin retrograde flow, consistent with increased force transmission across adhesion sites. NaBC1 stimulation also induces a coordinated increase in the expression of fibronectin-binding integrins, including 5{beta}1 and v{beta}3, at both transcriptional and protein levels. Proximity ligation assays reveal an enhanced spatial association between NaBC1 and these integrins at the cell membrane, supporting the formation of cooperative adhesion complexes. In parallel, fluorescently labelled boron accumulates at focal adhesions and within intracellular compartments such as mitochondria, lysosomes, and the endoplasmic reticulum, suggesting a link between NaBC1-dependent adhesion signaling and subcellular organization. Importantly, the adhesive and mechanotransductive effects driven by NaBC1 are strictly dependent on fibronectin integrity and are lost on mutant fibronectins lacking RGD or synergy motifs, as well as on laminin-111 substrates that do not support molecular clutch engagement. Together, these findings identify NaBC1 as an integral component of fibronectin-integrin adhesion systems, contributing to the regulation of myoblast mechanics and polarity through cooperative interactions with fibronectin-binding integrins.

bioengineering↗

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↗