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Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle.

ABSTRACT: Exercise prevents depression through peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC-1α)-mediated activation of a particular branch of the kynurenine pathway. From kynurenine (KYN), two independent metabolic pathways produce neurofunctionally different metabolites, mainly in somatic organs: neurotoxic intermediate metabolites via main pathway and neuroprotective end product, kynurenic acid (KYNA) via the branch. Elevated levels of KYN have been found in patients with depression. Herein, we investigated whether and how caffeine prevents depression, focusing on the kynurenine pathway. Mice exposed to chronic mild stress (CMS) exhibited depressive-like behaviours with an increase and decrease in plasma levels of pro-neurotoxic KYN and neuroprotective KYNA, respectively. However, caffeine rescued CMS-exposed mice from depressive-like behaviours and restored the plasma levels of KYN and KYNA. Concomitantly, caffeine induced a key enzyme converting KYN into KYNA, namely kynurenine aminotransferase-1 (KAT1), in murine skeletal muscle. Upon caffeine stimulation murine myotubes exhibited KAT1 induction and its upstream PGC-1α sustainment. Furthermore, a proteasome inhibitor, but not translational inhibitor, impeded caffeine sustainment of PGC-1α, suggesting that caffeine induced KAT1 by inhibiting proteasomal degradation of PGC-1α. Thus, caffeine protection against CMS-induced depression may be associated with sustainment of PGC-1α levels and the resultant KAT1 induction in skeletal muscle, and thereby consumption of pro-neurotoxic KYN.

SUBMITTER: Fang C

PROVIDER: S-EPMC8012704 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Sarcopenia, a critical loss of muscle mass and function because of the physiological process of aging, contributes to disability and mortality in older adults. It increases the incidence of pathologic fractures, causing prolonged periods of hospitalization and rehabilitation. The molecular mechanisms underlying sarcopenia are poorly understood, but recent evidence suggests that increased transforming growth factor-? (TGF-?) signaling contributes to impaired satellite cell function and muscle repair in aged skeletal muscle. We therefore evaluated whether antagonism of TGF-? signaling via losartan, an angiotensin II receptor antagonist commonly used to treat high blood pressure, had a beneficial impact on the muscle remodeling process of sarcopenic mice. We demonstrated that mice treated with losartan developed significantly less fibrosis and exhibited improved in vivo muscle function after cardiotoxin-induced injury. We found that losartan not only blunted the canonical TGF-? signaling cascade but also modulated the noncanonical TGF-? mitogen-activated protein kinase pathway. We next assessed whether losartan was able to combat disuse atrophy in aged mice that were subjected to hindlimb immobilization. We showed that immobilized mice treated with losartan were protected against loss of muscle mass. Unexpectedly, this protective mechanism was not mediated by TGF-? signaling but was due to an increased activation of the insulin-like growth factor 1 (IGF-1)/Akt/mammalian target of rapamycin (mTOR) pathway. Thus, blockade of the AT1 (angiotensin II type I) receptor improved muscle remodeling and protected against disuse atrophy by differentially regulating the TGF-? and IGF-1/Akt/mTOR signaling cascades, two pathways critical for skeletal muscle homeostasis. Thus, losartan, a Food and Drug Administration-approved drug, may prove to have clinical benefits to combat injury-related muscle remodeling and provide protection against disuse atrophy in humans with sarcopenia.

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Caffeine protects against stress-induced murine depression through activation of PPARγC1α-mediated restoration of the kynurenine pathway in the skeletal muscle.

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