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