Aging induces gradual accumulation of damages in cells and tissues, which leads to physiological dysfunctions. Aging-associated muscle dysfunction is commonly seen in aged population and severely affects their physical activity and life quality, against which aerobic training has been shown to exert antagonizing or alleviating effects. Circular RNAs (circRNAs) play important roles in various physiological processes, yet their involvement in aging-associated muscle dysfunction is not well understood. In this study, we performed comprehensive analysis of circRNAs profiles in quadriceps muscles in sedentary young and aging mice, as well as aging mice with aerobic exercise using RNA sequencing. Our results identified circRNAs altered by factors of aging and aerobic exercise. Their host genes were then predicted and analyzed by gene ontology enrichment analysis. Importantly, we found that circBBS9 featured decreased levels in aging compared to young mice and elevated expression in exercise versus sedentary aging mice. Besides, we performed GO and KEGG analysis on circBBS9 target genes, as well as established the circBBS9-miRNA-mRNAs interaction network. Our results indicate that circBBS9 may play active roles in muscle aging by mediating the benefits of aerobic training intervention, thus may serve as a novel therapeutic target combating aging-associated muscle dysfunction.

Aerobic exercise has been shown to play a crucial role in preventing neurological diseases and improving cognitive function. In the present study, we investigated the effect of treadmill training on retinal ganglion cells (RGCs) following optic nerve transection in adult rats. We exercised the rats on a treadmill for 5 d/week (30 min/d at a rate of 9 m/min) or placed control rats on static treadmills. After 3 weeks of exercise, the left optic nerve of each rat was transected. After the surgery, the rat was exercised for another week. The percentages of surviving RGCs in the axotomized eyes of inactive rats were 67% and 39% at 5 and 7 days postaxotomy, respectively. However, exercised rats had significant more RGCs at 5 (74% survival) and 7 days (48% survival) after axotomy. Moreover, retinal brain-derived neurotrophic factor (BDNF) protein levels were significantly upregulated in response to exercise compared with those in the axotomized eyes of inactive rats. Blocking BNDF signaling during exercise by intraperitoneal injections of ANA-12, a BDNF tropomyosin receptor kinase (TrkB) receptor antagonist, reduced the number of RGCs in exercised rats to the level of RGCs in the inactive rats, effectively abolishing the protection of RGCs afforded by exercise. The results suggest that treadmill training effectively rescues RGCs from neurodegeneration following optic nerve transection by upregulating the expression of BDNF.

Resistance exercise leads to improved muscle function and metabolic homeostasis. Yet how circadian rhythm impacts exercise outcomes and its molecular transduction remains elusive. Human volunteers were subjected to 4 weeks of resistance training protocols at different times of day to assess training outcomes and their associations with myokine irisin. Based on rhythmicity of Fibronectin type III domain containing 5 (FNDC5/irisin), we trained wild type and FNDC5 knockout mice at late active phase (high FNDC5/irisin level) or late rest phase (low FNDC5/irisin level) to analyze exercise benefits on muscle function and metabolic homeostasis. Molecular analysis was performed to understand the regulatory mechanisms of FNDC5 rhythmicity and downstream signaling transduction in skeletal muscle. In this study, we showed that regular resistance exercises performed at different times of day resulted in distinct training outcomes in humans, including exercise benefits and altered plasma metabolomics. We found that muscle FNDC5/irisin levels exhibit rhythmicity. Consistent with human data, compared to late rest phase (low irisin level), mice trained chronically at late active phase (high irisin level) gained more muscle capacity along with improved metabolic fitness and metabolomics/lipidomics profiles under a high-fat diet, whereas these differences were lost in FNDC5 knockout mice. Mechanistically, Basic helix-loop-helix ARNT like 1 (BMAL1) and Peroxisome proliferative activated receptor, gamma, coactivator 1 alpha 4 (PGC1α4) induce FNDC5/irisin transcription and rhythmicity, and the signaling is transduced via αV integrin in muscle. Together, our results offered novel insights that exercise performed at distinct times of day determines training outcomes and metabolic benefits through the rhythmic regulation of the BMAL1/PGC1α4-FNDC5/irisin axis.