Biology subjects

Castor-Macias, J. A.

Publications and source records attributed to Castor-Macias, J. A..

3 recordsLinked to original sources

bioRxiv2020

Sestrins regulate age-induced deterioration of muscle stem cell homeostasis

The health and homeostasis of skeletal muscle is preserved by a population of tissue resident stem cells called satellite cells. Young healthy satellite cells maintain a state of quiescence, but aging or metabolic insults results in reduced capacity to prevent premature activation and stem cell exhaustion. As such, understanding genes and pathways that protect satellite cell maintenance of quiescence are needed. Sestrins are a class of stress-inducible proteins that act as antioxidants and inhibit the activation of the mammalian target of rapamycin complex 1 (mTORC1) signaling complex. Despite these pivotal roles, the role of Sestrins has not been explored in adult stem cells. Herein, we show that Sestrin1,2 loss results in hyperactivation of the mTORC1 complex, increased propensity to enter the cell cycle and shifts in metabolic flux. Aging of Sestrin1,2 knockout mice demonstrated a loss of MuSCs and reduced ability to regenerate. These findings demonstrate Sestrins function to help maintain MuSC metabolism that supports quiescence and against aging. HighlightsO_LISestrin deficiency alters mTORC1 signaling in muscle stem cells (MuSCs). C_LIO_LIIn young mice, Sestrins are dispensable for regenerative responses of MuSCs. C_LIO_LISestrin deficiency accelerates age-dependent loss and dysfunction of MuSCs. C_LI

cell biology↗

bioRxiv2020

Lipidomic Profiling Reveals an Age-Related Deficiency of Skeletal Muscle Proresolving Mediators that Contributes to Maladaptive Tissue Remodeling

Chronic inflammation and deregulated acute immune cell responses to injury contribute to age-associated skeletal muscle dysfunction. Specialized pro-resolving mediators (SPMs) control inflammation and support myofiber regeneration in young mice, but their role in aging muscle remains unknown. Here we examined the effect of age on the mediator lipidome of skeletal muscle via LC-MS based lipidomic profiling and tested whether systemic administration of the SPM resolvin D1 (RvD1) could limit excessive inflammation and improve the regenerative capacity of aged muscle. Aged mice displayed chronic low-grade muscle inflammation prior to injury and this was associated with a basal deficiency of lipoxygenase (LOX) derived SPMs as well as anti-inflammatory cytochrome P450 (CYP) derived lipid epoxides. Following muscle damage, young and aged mice produced similar amounts of pro-inflammatory cyclooxygenase (COX) and 12-LOX metabolites, but aged mice mounted a markedly deficient SPM response. This was associated with heightened leukocyte recruitment, impaired myofiber regeneration, and delayed recovery of strength. Systemic treatment with RvD1 had minimal impact on excessive myeloid cell infiltration and defective myofiber regeneration in aged mice. Nevertheless, RvD1 treatment did suppress inflammatory cytokines, modulated muscle stem cells, limited maladaptive tissue remodeling, and improved recovery of specific muscle force. We conclude that aging results in a marked deficiency of local SPM biosynthesis within muscle and that immunoresolvents may be attractive novel therapeutics for the treatment of muscular injuries and associated pain in the elderly, due to positive effects on recovery of muscle function without the negative side effects on myofiber regeneration of traditional anti-inflammatory treatments.

immunology↗

bioRxiv2020

Immunoresolvents Support Skeletal Myofiber Regeneration via Actions on Myeloid and Muscle Stem Cells

Specialized pro-resolving mediators (SPMs) actively limit inflammation and expedite its resolution. Here we profiled intramuscular lipid mediators following injury and investigated the role of SPMs in skeletal muscle inflammation and repair. Both eicosanoids and SPMs increased following myofiber damage induced by intramuscular injection of barium chloride or functional overload. Daily systemic administration of resolvin D1 (RvD1) limited the degree and duration of inflammation, enhanced regenerating myofiber growth, and improved recovery of muscle strength. RvD1 suppressed inflammatory cytokines, enhanced polymorphonuclear cell clearance, modulated muscle stem cells, and polarized macrophages to a more pro-regenerative subset. RvD1 had minimal direct impact on in-vitro myogenesis but directly suppressed myokine production and stimulated macrophage phagocytosis, showing that SPMs influence modulate both infiltrating myeloid and resident muscle cells. These data reveal the efficacy of immunoresolvents as a novel alternative to classical anti-inflammatory interventions in the management of muscle injuries to modulate inflammation while stimulating tissue repair.

immunology↗