Abstract
Muscle function relies on the precise architecture of dynamic contractile elements, which must be fine-tuned to maintain motility throughout life. Muscle is also plastic, and remodeled in response to stress, growth, neural and metabolic inputs. The conserved muscle-enriched microRNA, miR-1, regulates distinct aspects of muscle development, but whether it plays a role during aging is unknown. Here we investigated Caenorhabditis elegans miR-1 in muscle function in response to proteostatic stress. mir-1 deletion improved mid-life muscle motility, pharyngeal pumping, and organismal longevity upon polyQ35 proteotoxic challenge. We identified multiple vacuolar ATPase subunits as subject to miR-1 control, and the regulatory subunit vha-13/ATP6V1A as a direct target downregulated via its 3'UTR to mediate miR-1 physiology. miR-1 further regulates nuclear localization of lysosomal biogenesis factor HLH-30/TFEB and lysosomal acidification. Our studies reveal that miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to impact muscle function and health during aging.
Highlights
Aging is the major cause of progressive decline in all organ systems throughout the body
We found that the mRNA levels of vha-5, vha-10, vha-13, and vha-19, as well as transcription factors hlh-30/TFEB and daf-16/FOXO, were increased approximately twofold in mir-1 mutants compared to age-matched WT worms (Figure 3A), consistent with the idea that these genes are miR-1 targets
We demonstrated that vha-13 expression is downregulated by miR-1 in muscle tissues via two distinct binding sites in its 30UTR
Summary
Aging is the major cause of progressive decline in all organ systems throughout the body. We observed that about 30% of the mir-1;Q35 mutants left the circle while only 2.5% of the control Q35 worms did so (Figure 1D, Supplementary file 1b). The motility of mir-1(gk276);Q40 worms, determined by 1 min thrashing assays, was unaffected at day 3 of adulthood and reduced in two out of three experiments at day 7 of adulthood compared to Q40 controls (Supplementary file 1b).
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