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Abstract The fibrogenic conversion of satellite cells contributes to the atrophy and fibrosis of skeletal muscle, playing a significant role in the pathogenesis of age-related sarcopenia. Melatonin, a hormone secreted by the pineal gland, exhibits anti-aging and anti-fibrotic effects in various conditions. However, the effect of melatonin on satellite cell fate and age-related sarcopenia remains under-explored. Here, we report that melatonin treatment mitigated the loss of muscle mass and strength in aged mice, replenished the satellite cell pool and curtailed muscle fibrosis. When primary SCs were cultured in vitro and subjected to aging induction via d-galactose, they exhibited a diminished myogenic potential and a conversion from myogenic to fibrogenic lineage. Notably, melatonin treatment effectively restored the myogenic potential and inhibited this lineage conversion. Furthermore, melatonin attenuated the expression of the fibrogenic cytokine, transforming growth factor-β1, and reduced the phosphorylation of its downstream targets Smad2/3 both in vivo and in vitro. In summary, our findings show melatonin's capacity to counteract muscle decline and inhibit fibrogenic conversion in aging SCs and highlight its potential therapeutic value for age-related sarcopenia. Graphical Abstract

Background: Skeletal aging is characterized by a decrease in bone mass and an increase in marrowfat content. Advanced oxidation protein products (AOPPs) accumulate easily with aging and disrupt redox homeostasis. We examined whether AOPPs accumulation contributes to the bone-fat imbalance during skeletal aging. Methods: Both young and aged mice were employed to assess the changes of AOPPs levels and its contribution to bone-fat imbalance during skeletal aging. Primary bone marrow mesenchymal stromal cells (MSCs) were used to examine the potential role of AOPPs in age-related switch between osteogenic and adipogenic differentiation. Aged mice were also gavaged by non-selective antioxidant N‐acetyl‐L‐cysteine (NAC), followed by close monitoring of the changes in AOPPs levels and bone-fat metabolism. Furthermore, young mice were chronically exposed to AOPPs and then evaluated for the changes of bone mass and marrow adiposity. Results: The levels of AOPPs in serum and bone marrow were markedly higher in aged mice than that in young mice. Age-related accumulation of AOPPs was accompanied by reduced bone formation, increased marrow adiposity and deterioration of bone microstructure. Reduced AOPPs accumulation by antioxidant NAC leaded to improvement of the bone-fat imbalance in aged mice. Similarly, the bone-fat imbalance was induced by chronic AOPPs loading in young mice. Compared with MSCs from young mice, MSCs from aged mice tended to differentiate into adipocytes rather than osteoblasts and displayed cellular senescence. Exposure of primary MSCs to AOPPs resulted in the switch from osteogenic to adipogenic lineage and cellular senescence. AOPPs challenge also increased intracellular ROS generation by the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase and mitochondria. The antioxidant NAC, after scavenging ROS, ameliorated the AOPPs-induced lineage switch and senescence in MSCs by inhibiting the PI3K/AKT/mTOR pathway. Conclusion: Our findings revealed the involvement of AOPPs in age‐related switch between osteogenic and adipogenic differentiation, and illuminated a novel potential mechanism underlying bone-fat imbalance during skeletal aging. The translational potential of this article: Reducing AOPPs accumulation and its cascading effects on MSCs might be an attractive strategy for delaying skeletal aging.

Abstract Background Increased oxidative stress contributes to enhanced osteoclastogenesis and age-related bone loss. Melatonin (MT) is an endogenous antioxidant and declines with aging. However, it was unclear whether the decline of MT was involved in the enhanced osteoclastogenesis during the aging process. Methods The plasma level of MT, oxidative stress status, bone mass, the number of bone marrow-derived monocytes (BMMs) and its osteoclastogenesis were analyzed in young (3-month old) and old (18-month old) mice (n = 6 per group). In vitro, BMMs isolated from aged mice were treated with or without MT, followed by detecting the change of osteoclastogenesis and intracellular reactive oxygen species (ROS) level. Furthermore, old mice were treated with MT for 2 months to investigate the therapeutic effect. Results The plasma level of MT was markedly lower in aged mice compared with young mice. Age-related decline in MT was accompanied by enhanced oxidative stress, osteoclastogenic potential and bone loss. MT intervention significantly suppressed the receptor activator of nuclear factor-κB ligand (RANKL)-induced osteoclastogenesis, decreased intracellular ROS and enhanced antioxidant capacity of BMMs from aged mice. MT supplementation significantly attenuated oxidative stress, osteoclastogenesis, bone loss and deterioration of bone microstructure in aged mice. Conclusions These results suggest that age-related decline of MT enhanced osteoclastogenesis via disruption of redox homeostasis. MT may serve as a key regulator in osteoclastogenesis and bone homeostasis, thereby highlighting its potential as a preventive agent for age-related bone loss.

Emerging evidence shows that KRAS-mutant colorectal cancer (CRC) depends on glutamine (Gln) for survival and progression, indicating that targeting Gln metabolism may be a promising therapeutic strategy for KRAS-mutant CRC. However, the precise mechanism by which Gln metabolism reprogramming promotes and coordinates KRAS-mutant CRC progression remains to be fully investigated. Here, we discovered that solute carrier 25 member 21 (SLC25A21) expression was downregulated in KRAS-mutant CRC, and that SLC25A21 downregulation was correlated with poor survival of KRAS-mutant CRC patients. SLC25A21 depletion selectively accelerated the growth, invasion, migration, and metastasis of KRAS-mutant CRC cells in vitro and in vivo, and inhibited Gln-derived α-ketoglutarate (α-KG) efflux from mitochondria, thereby potentiating Gln replenishment, accompanied by increased GTP availability for persistent KRAS activation in KRAS-mutant CRC. The restoration of SLC25A21 expression impaired the KRAS-mutation-mediated resistance to cetuximab in KRAS-mutant CRC. Moreover, the arrested α-KG efflux that occurred in response to SLC25A21 depletion inhibited the activity of α-KG–dependent DNA demethylases, resulting in a further decrease in SLC25A21 expression. Our studies demonstrate that SLC25A21 plays a significant role as a tumor suppressor in KRAS-mutant CRC by antagonizing Gln-dependent anaplerosis to limit GTP availability for KRAS activation, which suggests potential alternative therapeutic strategies for KRAS-mutant CRC.