Gohlke, S. | Search bioRxiv

bioRxiv2023

Aging impairs muscle regeneration by desynchronizing matrix mechano-signaling and macrophage immunomodulation via fibro-adipogenic progenitors

Skeletal muscle regeneration depends on the function of fibro/adipogenic progenitors (FAPs). Here we show that aging impairs myogenic stem cells by disrupting the integration of extracellular matrix and immunomodulatory functions within the stem cell niche, thereby promoting fibro/fatty degeneration. We identify the FAP-secreted protein Periostin as a niche factor that is decreased in aged muscle and in circulation of aged humans with low-exercise lifestyle. Periostin controls FAP-expansion after injury and its depletion fate-regulates FAPs towards adipogenesis. This leads to delayed pro- to anti-inflammatory macrophage transition during regeneration. Transplantation of young FAPs with high Periostin secretion, but not Periostin-deficient FAPs, into aged muscle restores inflammation resolution and successful regeneration. Mechanistically, Periostin activates Focal adhesion kinase- and AKT-signaling in macrophages via integrins to promote an anti-inflammatory profile, which synchronizes matrix-derived mechanosensory signaling and immunomodulation. These results uncover a novel role of FAP-based regulation that orchestrates successful muscle regeneration and prevents fibro/fatty degeneration.

physiology↗

bioRxiv2022

Cold-induced expression of a truncated Adenylyl Cyclase 3 acts as rheostat to brown fat function.

Promoting brown adipose tissue (BAT) activity has been recognized as innovative therapeutic approach to improve obesity and metabolic disease. Whilst the molecular circuitry underlying thermogenic activation of BAT is well understood, the processes underlying rheostatic regulation of BAT to maintain homeostasis and avoid excessive energy dissipation remain ill-defined. Increasing cyclic AMP (cAMP) biosynthesis is key for BAT activation. Here, we demonstrate that ADCY3, an adenylyl cyclase whose expression is induced during cold exposure and regulates cAMP homeostasis in thermogenic fat, is dispensable for BAT function in lean mice, but becomes critical during obesity. Furthermore, by combining RNA-seq with epigenomic H3K4me3 profiling, we detected a novel, cold-inducible promoter that generates a 5 truncated Adcy3-at mRNA isoform, Adcy3-at. Mice lacking only Adcy3-at, but not full-length Adcy3, displayed increased energy expenditure already under lean conditions and were protected against obesity and ensuing metabolic imbalances. Subcellularly, translated ADCY3-AT proteins are retained in the endoplasmic reticulum (ER), did not translocate to the cell membrane, and lacked enzymatic activity. By interacting with ADCY3, ADCY3-AT retained ADCY3 in the ER and, thereby, reduced the plasma membrane pool of ADCYs available for G-protein mediated cAMP synthesis. Thereby, ADCY3-AT acts as a signaling rheostat in BAT, limiting adverse consequences of uncurbed cAMP activity after long-term BAT activation. Adcy3-at induction was driven by a cold-induced, truncated isoform of the transcriptional cofactor PPARGC1A (PPARG Coactivator 1 Alpha, PPARGC1A-AT). Expression of Ppargc1a-at and Adcy3-at are evolutionary conserved, indicating that transcriptional rewiring by commissioning of alternative promoters is key for thermogenic fat function.

cell biology↗