Biology subjects

Adegoke, O. A. J.

Publications and source records attributed to Adegoke, O. A. J..

4 recordsLinked to original sources

bioRxiv2025

DIfferential Branched-Chain Amino Acid Metabolism in Tissues of Tumour-Bearing Mice

Cancer cachexia is a multifactorial syndrome characterized by the involuntary loss of skeletal muscle and adipose tissue, often resistant to nutritional support. The branched-chain amino acids (BCAA: leucine, isoleucine, and valine) stimulate protein synthesis, yet BCAA-targeted therapies have yielded limited clinical benefit, and inconsistent results. In this study, a C26 colon cancer mouse model was used to examine how tumor burden alters BCAA metabolism across skeletal muscle, liver, kidney, and adipose tissue. Tumors accumulated BCAA and showed increased oxidation of these amino acids, whereas peripheral sites displayed widespread BCAA depletion, reduced expression of the amino acid (AA) transporter LAT1, and suppression of mechanistic target of rapamycin complex 1 (mTORC1) signaling. Notably, the soleus muscle maintained mTORC1 activity despite reduced BCAA availability, suggesting fiber-type-specific adaptations. These findings indicate that tumors act as metabolic sinks, diverting systemic AA away from host tissues. Such reprogramming may underlie the limited success of BCAA-based interventions in cachexia and highlight the need for therapies that address both tumor and host metabolism. New and NoteworthyThis is the first study to profile branched-chain -keto acid (BCKA) levels together with branched-chain amino acid (BCAA) metabolism across multiple tissues in a cancer cachexia model. Tumors accumulated BCAA while some peripheral sites showed depletion, and all peripheral tissues exhibited reduced expression of the transporter LAT1. These tissue-specific adaptations reveal systemic metabolic reprogramming and may explain the limited efficacy of BCAA-based therapies.

physiology↗

bioRxiv2025

Effect of Age and Sex on BCAA Metabolism in Mice

Increased plasma levels of branched-chain amino acids (BCAA) have been implicated in insulin resistance. This condition worsens with age, but plasma BCAA levels are downregulated in old men. The effect of age and/ sex on BCAA metabolism has been rarely studied. Thus, the objective of this study was to analyze how age and sex affect BCAA levels and their metabolism in mouse tissues. Male and female young (4-month) and old (18-months) CD2F1 mice were used. BCAA levels and relevant BCAA metabolic enzymes abundance/activity in plasma, muscle, liver, adipose tissue, and heart were analyzed. Old males exhibited greater plasma BCAA concentrations compared to young males and old females, but plasma branched-chain ketoacid (BCKA) levels were lower in old mice in both sexes. Intracellular BCAA levels were lower in skeletal muscle and heart from old mice independent of sex. There was an age-sex interaction in the lever in that reduced total BCAA was seen only in old male animals. In adipose tissue, total BCKA levels were higher in old male animals. Skeletal muscle abundance of the BCAA transporter LAT1 was reduced in old females compared to young females. In the liver, female mice had higher levels of LAT1 than male mice independent of age, while total BCKD was reduced in old females compared to old males. Pp2Cm levels were reduced in old animals independent of sex. In conclusion, while there were some changes in plasma and tissue BCAA/BCKA levels in response to age/sex, such changes were largely not consistent with changes in tissue BCAA catabolic enzyme abundance/activity. This suggests that protein levels of BCAA catabolic enzymes are preserved in aging in healthy animals and likely only become dysregulated in disease states.

physiology↗

bioRxiv2025

Sex Differences in Cachexia Outcomes and Branched-Chain Amino Acid Metabolism Following Chemotherapy in Aged Mice

Cachexia is a complex muscle wasting syndrome that affects majority of hospitalized cancer patients receiving chemotherapy. It is often unresponsive to nutritional interventions, including provision of branched-chain amino acids (BCAA: leucine, isoleucine and valine). BCAA are anabolic for skeletal muscle. We wondered whether their ineffectiveness in managing cachexia might be related to altered metabolism of these amino acids, a subject that has received minimal attention. Because estrogen limits BCAA catabolism, we hypothesized that the effects of chemotherapy on cachexia in old mice would be worse in males compared to females, and that this would be related to greater tissue release of BCAA in males. To better reflect age population for which cachexia is an issue, we treated aged male and female mice (18{+/-}2 months) with the chemotherapy drug cocktail FOLFIRI (50mg/kg 5-fluorouracil (5FU), 90mg/kg Leucovorin, and 24mg/kg CPT11) or vehicle twice per week for 6 weeks. This cocktail is used in treating colon cancer. Metabolism and concentrations of the BCAA and their metabolites were measured in plasma and tissues. There was a main effect of chemotherapy, reflected in reduced body weight, skeletal muscle, myofibrillar protein content, anabolic signalling and protein synthesis. In response to chemotherapy, males showed worsened outcomes for skeletal muscle weight and ubiquitinated proteins; they also had higher total plasma BCAA but reduced muscle BCAA. There was a main effect of chemotherapy in reducing the expression of the BCAA transporter LAT1. In response to chemotherapy, gastrocnemius muscle of males but not females had reduced inhibitory phosphorylation of BCKD-E1ser293, corresponding with increased activity of this enzyme. Chemotherapy reduced muscle and liver ketoacids of the BCAA only in females. These data suggest that sex differences in BCAA catabolism may be linked to the severity of chemotherapy-induced muscle damage and interventions against cachexia need to take this into account.

physiology↗

bioRxiv2025

Myofibrillar protein accumulation but reduced protein synthesis in PDCD4-depleted myotubes

Skeletal muscle is critical to whole-body functionality and homeostasis. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a nutrient/growth-factor sensitive positive regulator of skeletal muscle mass. Amongst other substrates, mTORC1 phosphorylates the ribosomal protein S6 kinase (S6K1). Activated S6K1 acts through multiple effectors, including programmed cell death 4 (PDCD4), to activate mRNA translation and protein synthesis. Much of what is known about PDCD4 is in non-muscle cells. We previously demonstrated that the effect of PDCD4 differs between myoblasts and myotubes. Here, we showed that PDCD4 depletion in L6 and C2C12 myotubes enhanced myotube diameter (+36%) and accumulation of myofibrillar proteins (+163 - 237%). These effects occurred along with increased phosphorylation of AKTser473 (+85%) and of the mTORC1 substrate S6K1thr389 (+152%), but protein synthesis was suppressed. There was increased phosphorylation of FoxO3aser253 (+250%) and a corresponding reduction in the expression of the muscle protein ubiquitin ligase MuRF1 (-44%), but there was no significant effect on measures of proteolysis or autophagy. In starved myotubes treated with the proteasome inhibitor MG132, accumulation of ubiquitinated proteins was attenuated in PDCD4-depleted cells. PDCD4 depletion did not augment measures of myotube contraction but was associated with reduced ATP and intracellular amino acid levels. Finally, AKT inhibition partially attenuated the effect of PDCD4 depletion on myofibrillar protein abundance. In summary, myofibrillar protein accumulation in PDCD 4-depleted myotubes did not lead to improved myotube function, likely due to reduced energy level. Our data point to a pivotal role for PDCD4 in regulating myotube size and metabolism.

physiology↗