NAD+ boosting reduces age-associated amyloidosis and restores mitochondrial homeostasis in muscle.

Aging is characterized by loss of proteostasis and mitochondrial homeostasis. Here, we provide bioinformatic evidence of dysregulation of mitochondrial and proteostasis pathways in muscle aging and diseases. Moreover, we show accumulation of amyloid-like deposits and mitochondrial dysfunction during natural aging in the body wall muscle of C. elegans, in human primary myotubes, and in mouse skeletal muscle, partially phenocopying inclusion body myositis (IBM). Importantly, NAD+ homeostasis is critical to control age-associated muscle amyloidosis. Treatment of either aged N2 worms, a nematode model of amyloid-beta muscle proteotoxicity, human aged myotubes, or old mice with the NAD+ boosters nicotinamide riboside (NR) and olaparib (AZD) increases mitochondrial function and muscle homeostasis while attenuating amyloid accumulation. Hence, our data reveal that age-related amyloidosis is a contributing factor to mitochondrial dysfunction and that both are features of the aging muscle that can be ameliorated by NAD+ metabolism-enhancing approaches, warranting further clinical studies.

Enoxacin induces oxidative metabolism and mitigates obesity by regulating adipose tissue miRNA expression.

MicroRNAs (miRNAs) have been implicated in oxidative metabolism and brown/beige adipocyte identity. Here, we tested whether widespread changes in miRNA expression promoted by treatment with the small-molecule enoxacin cause browning and prevent obesity. Enoxacin mitigated diet-induced obesity in mice, and this was associated with increased energy expenditure. Consistently, subcutaneous white and brown adipose tissues and skeletal muscle of enoxacin-treated mice had higher levels of markers associated with thermogenesis and oxidative metabolism. These effects were cell autonomous since they were recapitulated in vitro in murine and human cell models. In preadipocytes, enoxacin led to a reduction of miR-34a-5p expression and up-regulation of its target genes (e.g., Fgfr1, Klb, and Sirt1), thus increasing FGF21 signaling and promoting beige adipogenesis. Our data demonstrate that enoxacin counteracts obesity by promoting thermogenic signaling and inducing oxidative metabolism in adipose tissue and skeletal muscle in a mechanism that involves, at least in part, miRNA-mediated regulation.