Lysosomal Function Impacts the Skeletal Muscle Extracellular Matrix

Abstract

Muscle development and homeostasis are critical for normal muscle function. A key aspect of muscle physiology during development, growth, and homeostasis is modulation of protein turnover, the balance between synthesis and degradation of muscle proteins. Protein degradation depends upon lysosomal pH, generated and maintained by proton pumps. Sphingolipid transporter 1 (spns1), a highly conserved gene encoding a putative late endosome/lysosome carbohydrate/H+ symporter, plays a pivotal role in maintaining optimal lysosomal pH and spns1−/− mutants undergo premature senescence. However, the impact of dysregulated lysosomal pH on muscle development and homeostasis is not well understood. We found that muscle development proceeds normally in spns1−/− mutants prior to the onset of muscle degeneration. Dysregulation of the extracellular matrix (ECM) at the myotendinous junction (MTJ) coincided with the onset of muscle degeneration in spns1−/− mutants. Expression of the ECM proteins laminin 111 and MMP-9 was upregulated. Upregulation of laminin 111 mitigated the severity of muscle degeneration, as inhibition of adhesion to laminin 111 exacerbated muscle degeneration in spns1−/− mutants. MMP-9 upregulation was induced by tnfsf12 signaling, but abrogation of MMP-9 did not impact muscle degeneration in spns1−/− mutants. Taken together, these data indicate that dysregulated lysosomal pH impacts expression of ECM proteins at the myotendinous junction.

Spns1-dependent endocardial lysosomal function drives valve morphogenesis through Notch1-signaling

“…3A-C). Consistent with previous observations in the nrs yolk (Young et al , 2002; Sasaki et al , 2014) and skeletal muscle (Coffey et al , 2021), we found a significant accumulation of mRFP + -autolysosomes, LysoTracker™-vesicles and lamp2 + -lysosomes in the mutant heart at 3 days post-fertilization (dpf, Fig. 3D), where both autophagosomes/autolysosomes and lysosomes were particularly enriched and enlarged in the OFT and AVC regions compared to siblings (Fig.…”

“…spns1 encodes a lipid-transporter that affects lysosomal acidity and, consequently, the function of pH-dependent lysosomal proteases (He et al, 2022;Scharenberg et al, 2023). The nrs mutant is a thoroughly characterized model of lysosomal-function impairment, which has allowed to study lysosomal deficiency in the contexts of embryogenesis (Young et al, 2002), senescence (Sasaki et al, 2014(Sasaki et al, , 2017 and muscle degeneration (Coffey et al, 2021). Interestingly, the human spns1 locus is located within the chromosome region 16p11.2, a region that has been associated with myxomatous mitral valve prolapse (Disse et al, 1999), aortic valve abnormalities (Ghebranious et al, 2007), septal defects and coarctation of aorta (Li et al, 2017).…”

SPNS1 ablation drives skeletal muscle atrophy by disrupting mitophagy, mitochondrial function, and apoptosis in mice

“…Coffey et al found that loss of SPNS1 dysregulated lysosomal pH, which impacts the expression of extracellular matrix proteins at the myotendinous junction in zebrafish. 4 In this study, we demonstrate that ablation of SPNS1 in skeletal muscle results in impaired lysosomal digestion, hindering mitophagy and triggering the accumulation of abnormal mitochondria. As a result, damaged mitochondria cannot be cleared, leading to the leakage of pro-apoptotic protein and the activation of apoptosis.…”