Perturbation of multi-molecular complexes in skeletal muscle induces protective proteases in the CNS that degrade pathogenic proteins

ABSTRACT: ABSTRACT. Many cellular functions are ensured by the activity of multimolecular complexes and homeostatic mechanisms ensure their stoichiometric assembly. Disruption of individual complex components can perturb this process and induce local adaptive responses. In addition to cell-autonomous effects, such surveillance systems are also active at the organismal level: cellular stress in one tissue can be sensed systemically and lead to adaptive responses in other tissues during aging and disease, as found for muscle-to-central nervous system (CNS) stress signaling, Here, we have examined the local and systemic stress responses induced by the genetic perturbation of distinct molecular complexes, i.e. the sarcomere, mitochondrial complex I, proteasome, and VCP (valosin-containing protein) complex. Surprisingly, we find that a conserved stress response is induced locally in muscle and systemically following the muscle-specific RNAi for components of these diverse multimolecular complexes. These local and systemic responses are centered on the transcriptional induction of proteases and peptidases, many of which can degrade an aggregation-prone model protein, huntingtin-polyQ. The myokine Amyrel is a possible mediator of this muscle-to-CNS signaling because it was previously found to be triggered by proteasome stress in muscle and to regulate protease expression in the CNS. In agreement with this model, here we find that Amyrel expression is induced by perturbation of diverse multimolecular complexes. Moreover, Amyrel induction in muscle reduces pathogenic huntingtin-polyQ aggregates in the retina. These findings therefore suggest that Amyrel contributes to reshaping CNS proteostasis in response to perturbation of multimolecular complexes in skeletal muscle. Altogether, our study provides insight into a muscle-to-CNS systemic response that conveys the status of multimolecular complexes of skeletal muscle.

ORGANISM(S): Drosophila melanogaster

PROVIDER: GSE299453 | GEO | 2025/10/22

REPOSITORIES: GEO