The NLRP3 inflammasome contributes to sarcopenia and lower muscle glycolytic potential in old mice

Abstract

The mechanisms underpinning decreased skeletal muscle strength and slowing of movement during aging are ill-defined. "Inflammaging," increased inflammation with advancing age, may contribute to aspects of sarcopenia, but little is known about the participatory immune components. We discovered that aging was associated with increased caspase-1 activity in mouse skeletal muscle. We hypothesized that the caspase-1-containing NLRP3 inflammasome contributes to sarcopenia in mice. Male C57BL/6J wild-type (WT) and NLRP3 mice were aged to 10 (adult) and 24 mo (old). NLRP3 mice were protected from decreased muscle mass (relative to body mass) and decreased size of type IIB and IIA myofibers, which occurred between 10 and 24 mo of age in WT mice. Old NLRP3 mice also had increased relative muscle strength and endurance and were protected from age-related increases in the number of myopathic fibers. We found no evidence of age-related or NLRP3-dependent changes in markers of systemic inflammation. Increased caspase-1 activity was associated with GAPDH proteolysis and reduced GAPDH enzymatic activity in skeletal muscles from old WT mice. Aging did not alter caspase-1 activity, GAPDH proteolysis, or GAPDH activity in skeletal muscles of NLRP3 mice. Our results show that the NLRP3 inflammasome participates in age-related loss of muscle glycolytic potential. Deletion of NLRP3 mitigates both the decline in glycolytic myofiber size and the reduced activity of glycolytic enzymes in muscle during aging. We propose that the etiology of sarcopenia involves direct communication between immune responses and metabolic flux in skeletal muscle.

Metabolic regulation of NLRP3

“…Recent evidence supports NLRP3 activity as detrimental mediator of sarcopenia. While no evidence was found for NLRP3 activity in an inflammatory setting, NLRP3‐mediated caspase‐1 activation promotes Glyceraldehyde 3‐phosphate dehydrogenase (GAPDH) proteolysis, resulting in decreased glycolytic potential as a mechanism of decreased skeletal muscle in aging, further limiting glucose metabolism in the aging process. Caspase‐1 activation has also been linked to cleavage of other glycolytic enzymes in muscle tissue .…”

Targeting macrophage scavenger receptor 1 promotes insulin resistance in obese male mice

“…; McBride et al. ). However, some PRRs protect against metabolic inflammation and insulin resistance during obesity (Denou et al.…”

“…Pattern recognition receptors (PRR) can bridge potential triggers of inflammation to metabolic outcomes by acting as sensors of pathogen-associated molecular patterns (PAMPs) and/ or damage-associated molecular patterns (DAMPs). There are many examples of PRRs propagating metabolic inflammation and promoting insulin resistance and defects in carbohydrate metabolism during aging, obesity, or other stressors (Shi et al 2006;Schertzer et al 2011;Vandanmagsar et al 2011;Henriksbo et al 2014;Bauernfeind et al 2016;McBride et al 2017). However, some PRRs protect against metabolic inflammation and insulin resistance during obesity (Denou et al 2015;Cavallari et al 2017).…”

Metabolic regulation of inflammasomes in inflammation

“…The degradation of glycolytic enzymes leads to a lower rate of glycolysis, which is in contrast with the common perception that activated macrophages exert a pro‐inflammatory function with increased glycolysis; thus, the reduction in glycolysis may explain the shift towards pyroptosis . NLRP3 inflammasome activation is correlated with GAPDH proteolysis in mouse skeletal muscle during ageing . Because fatty acid metabolism plays diverse roles in mediating inflammasome activation, tight constraints are essential for maintaining the balance between different lipid mediators.…”

“…106 NLRP3 inflammasome activation is correlated with GAPDH proteolysis in mouse skeletal muscle during ageing. 107 Because fatty acid metabolism plays diverse roles in mediating inflammasome activation, tight constraints are essential for maintaining the balance between different lipid mediators. For example, an eicosanoid storm that facilitates neutrophil recruitment is induced via caspase-1-dependent Ca 2+ influx that subsequently activates Ca 2+ -dependent cytosolic phospholipase A2 (cPLA2) during NAIP5/NLRC4 inflammasome activation.…”