miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to impact proteotoxicity and muscle function during aging

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.

Mitophagy and mitochondrial dynamics in type 2 diabetes mellitus treatment

“…The member of the microphthalmia family of basic helix-loop -helix-leucine-zipper (bHLH-Zip) including transcription factor EB (TFEB), transcription factor E3(TFE3) as well as a microphthalmia-associated transcription factor (MITF) participate in the mitochondrial dynamics in the kinase PINK1 and ubiquitin ligase Parkin -dependent manner [ 105 ]. Furthermore, TFEB also controls lysosome biogenesis and coordinating the lysosomal functions [ 106 ]. For instance, ATPase pumps (ATP6V1H, Na+/K- ATPase) and lysosomal membrane proteins (LAMP1 and LAMP2) and lysosomal proteases (cathepsin D, cathepsin B).…”

DAF-2/insulin IGF-1 receptor regulates motility during ageing by integrating opposite signaling from muscle and neuronal tissues

“…Our results do not exclude the existence of a secondary signal from muscle to neurons that could improve motility. Indeed, previous work has identified the miRNA mir-1 , as a regulator of a retrograde signal from muscle to neurons that modulates neuronal activity (Simon et al 2008) and mir-1 inactivation improves worm motility under pathological conditions (Schiffer et al 2021). Interestingly, mammalian SRF has been shown to negatively regulate mir-1 expression (Zhang et al 2011; Tritsch et al 2013).…”

The Role of MicroRNAs in Proteostasis Decline and Protein Aggregation during Brain and Skeletal Muscle Aging

“…In the context of age-related protein aggregation, miR-1 was shown to regulate muscle function and improve pharyngeal pumping in response to proteotoxic stress over time, while also suppressing polyglutamine 35 (polyQ35) protein aggregation in C. elegans [ 30 ]. A v-ATPase subunit, vha-13 was identified as a direct target of miR-1, which regulates lysosomal biogenesis and function [ 30 ]. Thus, miR-1 should be studied as a putative therapeutic strategy for combating muscle-specific protein aggregation and improving muscle motility across the lifespan.…”

“…Notably, studies in centenarians have provided more knowledge about how dynamic human miRNA profiles are throughout aging [ 27 , 28 ] For instance, increased biogenesis of miRNAs is observed in centenarians compared with octogenarians [ 29 ]. More recent studies showed that miRNAs regulate age-associated processes, and some evidence links miRNAs to protein aggregation in mammalian tissues, namely in the brain and skeletal muscle [ 30 , 31 ].…”