Physiologically relevant lactate accumulation from exercise or peripheral injection does not alter central or peripheral appetite signaling in mice.

Lactate has been implicated in exercise-induced appetite suppression though little work has explored the mechanisms underpinning its role. Recent work suggests lactate accumulation via exercise and intracerebroventricular injection can alter central appetite regulating pathways, though a supraphysiological dose of lactate was administered centrally and there was no assessment of peripheral appetite markers. Therefore, we examined how physiologically relevant lactate accumulation via exercise or intraperitoneal injection altered central and peripheral appetite signaling pathways and whether the lactate dehydrogenase inhibitor oxamate could blunt any exercise effect. Forty 10-week-old C57BL/6 J male mice (n = 10/group) were assigned to either: 1) sedentary (SED + SAL; saline); 2) exercise (EX+SAL; saline); 3) exercise with oxamate (EX+OX; 750 mg‧kg-1 body mass); or 4) lactate (SED + LAC; 1.0 g‧kg-1 body mass). Blood, stomach, and hypothalamus samples were collected ∼2 h post-exercise/injection. Though oxamate blunted exercise-induced lactate accumulation compared to the EX+SAL condition (P = 0.044, d = 0.73), there were no differences in circulating acylated ghrelin or stomach ghrelin O-acyltransferase content between groups (P > 0.213, ηp2<0.125). There were also no differences in hypothalamic content for neuropeptide Y, proopiomelanocortin, agouti-related peptide, and alpha melanocyte-stimulating hormone (P > 0.150, ηp2<0.170). Exercise did increase phosphorylated-total signal transducer and activator of transcription 3 (pSTAT3) compared to EX+OX (p = 0.065, d = 1.23) but there were no differences in other markers of lactate signaling: phosphorylated-total adenosine monophosphate activated protein kinase, and protein kinase b (P > 0.121, ηp2<0.160). Our results suggest that lactate accumulation due to exercise or peripheral injection does not alter central or peripheral appetite signaling when measured 2 h post-exercise/injection, though pSTAT3 was blunted with oxamate.

Lactate increases ADAM10 activity and reduces BACE1 activity in mouse brain.

The accumulation and aggregation of beta-amyloid (Aß) peptides contributes to neuronal dysfunction and death. These Aß peptides originate from a transmembrane protein known as amyloid precursor protein (APP), which can be processed via two competing pathways. Alpha-secretase (ADAM10) cleavage is thought to be neuroprotective while beta-secretase (BACE1) cleavage results in the production of Aß. Aerobic exercise reduces BACE1 activity, but the mechanisms involved are unknown though several exercise-induced mediators such as lactate may be involved. The current study examined whether systemic lactate can alter APP processing and BACE1 and ADAM10 activity. Mice were randomly assigned to one of four groups (n = 10 per group): (1) sedentary; (2) lactate-injection (1.0 g kg-1 body mass); (3) exercise; and (4) exercise and oxamate (lactate dehydrogenase inhibitor; 750 mg kg-1 body mass). Two hours following intervention, the hippocampus and prefrontal cortex (PFC) were collected. In the PFC lactate-injection and exercise resulted in higher ADAM10 activity compared to sedentary (exercise P = 0.0215, lactate P = 0.0038), in the hippocampus lactate-injection was higher compared to sedentary (lactate P = 0.011), and this was absent in the presence of oxamate. Hippocampal BACE1 activity was lower in the lactate group compared to the exercise group (P = 0.01). Oxamate resulted in higher BACE1 protein content compared to sedentary in the PFC (vs. sedentary P = 0.048). These findings suggest that lactate is important for regulating ADAM10 activity and thereby shifts APP processing away from Aß production. KEY POINTS: Exercise is known to alter the processing of amyloid precursor protein by reducing the activity of the rate-limiting enzyme BACE1 and increasing the activity of ADAM10. It is thought that exercise-induced factors are responsible for these enzymatic changes. This study examined if lactate accumulation plays a role in this process. Mice were assigned to one of four groups: sedentary, lactate, exercise and exercise + lactate. The findings demonstrate that lactate accumulation alters brain BACE1 and ADAM10 and shifts amyloid precursor protein processing away from beta-amyloid production.

Gestational physical activity alters offspring brain APP processing in an age-specific manner.

Maternal exercise is beneficial for offspring brain development. Amyloid precursor protein (APP) influences neurogenesis and synaptic plasticity. Cleavage products of APP are implicated in the proliferation of neural progenitor cells and neuronal network development. Our study aimed to investigate differences in APP processing in active or sedentary offspring of dams who were exposed to voluntary wheel running with and without a western diet throughout gestation. Female Wistar rats (7-8 weeks old) were fed a normal chow or western diet and randomized into voluntary wheel run or sedentary conditions. Dams returned to sedentary conditions post-parturition. The pups were weaned at 6 weeks after which point half of the samples were collected, while the rest of the pups remained on a normal diet, separated into sedentary or voluntary wheel run groups, and collected 12 weeks later. In-utero exposure to maternal exercise was associated with higher neuronal nuclear protein, higher soluble APPα and lower soluble APPß in offspring prefrontal cortex tissue at 6, but not 18 weeks of age. Neuronal nuclear protein is exclusive to mature neurons implying that offspring of mothers who exercised could have more neuron maturation potentially influenced by the higher APPα content at this early developmental stage. The voluntary wheel run offspring groups had a higher mature/pro brain derived neurotrophic factor ratio compared to the sedentary counterparts. The maternal effects were isolated to the juvenile 6-week-old pups, while the differences in the adult offspring were caused by their own exercise status.

Carnosic Acid (CA) Induces a Brown Fat-like Phenotype, Increases Mitochondrial Biogenesis, and Activates AMPK in 3T3-L1 Adipocytes.

Adipose tissue plays a crucial role in regulating metabolic homeostasis, and its dysfunction in obesity leads to insulin resistance and type 2 diabetes (T2D). White adipose tissue (WAT) primarily stores energy as lipids, while brown adipose tissue (BAT) regulates thermogenesis by dissipating energy as heat. The process of browning involves the transdifferentiation of WAT into brown-like or beige adipocytes, which exhibit a similar phenotype as BAT. The browning of WAT is an attractive approach against obesity and T2D, and the activation of the energy sensor AMP-activated protein kinase (AMPK) has been shown to play a role in browning. Carnosic acid (CA), a polyphenolic diterpene, found in many plants including rosemary, is reported to possess potent antioxidant, anti-inflammatory, and anti-hyperglycemic properties. The limited evidence available indicates that CA activates AMPK and may have anti-obesity and antidiabetic potential; however, the effects in adipocyte browning remain largely unexplored. This study aimed to examine the effects of CA on the markers of adipocyte browning. The treatment of 3T3L1 adipocytes with CA activated AMPK, reduced lipid accumulation, and increased the expression of browning protein markers (UCP-1, PGC-1α, PRDM16, and TFAM) and mitochondrial biogenesis. The use of compound C, an AMPK inhibitor, significantly attenuated the effects of CA, indicating AMPK involvement. These studies demonstrate that CA can activate AMPK and stimulate the browning of white adipocytes. Future animal and human studies are required to examine the effects of CA in vivo.

The effects of supplemental instruction derived from peer leaders on student outcomes in undergraduate human anatomy.

Supplemental instruction (SI) confers student success, as represented by grades, knowledge retention, and student engagement. However, studies often report professional, not undergraduate, program findings. To measure these effects, students studying human anatomy at a university in Ontario, Canada, attended structured (peer-assisted) or unstructured (nonpeer-assisted) SI sessions and completed a pre-/post-survey. Fifty-eight learners (39 systems (SYS) and 19 musculoskeletal (MSK) anatomy) completed both surveys and had responses analyzed. Both cohorts, maintained initial perceptions across pre-/post-analyses (MSK p = 0.1376 and SYS p = 0.3521). Resource usage was similar across both cohorts with discrepancies in skeletal model and textbook use. No MSK learner ranked any lab resources as "not at all useful." MSK learners felt more prepared to write a graded assessment (p = 0.0269), whereas SYS learners did not (p = 0.0680). Stratification of learners in MSK and SYS revealed learners spending between 30 and 60 min in SI sessions during the study period had the highest grades compared to students who spent less than 30 (p = 0.0286) or more than 60 (p = 0.0286) min attending SI sessions, respectively. Most learners in MSK (89.4%) and SYS (66%) concluded that they preferred structured over unstructured SI. Sentiment/thematic analysis using a generative AI-driven large language model revealed learners held positive perceptions of SI, emphasizing structured learning, resources, personalized learning, and support offered as the most prevalent themes surrounding SI. Ultimately, this study provides evidence that supports SI for improving student outcomes related to perceived preparedness for completing assessments and preferred teaching/learning styles in undergraduate human anatomy.

Characterizing the effects of muscle-specific GSK3α/ß reduction on murine muscle contractility and metabolism in female mice.

Dysregulation of skeletal muscle morphology and metabolism is associated with chronic diseases such as obesity and type 2 diabetes. The enzyme glycogen synthase kinase 3 (GSK3) is highly involved in skeletal muscle physiology and metabolism, acting as a negative regulator of muscle size, strength, adaptive thermogenesis, and glucose homeostasis. Correspondingly, we have shown that partial knockdown (∼40%) of GSK3 specifically in skeletal muscle increases lean mass, reduces fat mass, and activates muscle-based adaptive thermogenesis via sarco(endo)plasmic reticulum Ca2+ (SERCA) uncoupling in male mice. However, the effects of GSK3 knockdown in female mice have yet to be investigated. Here, we examined the effects of muscle-specific GSK3 knockdown on body composition, muscle size and strength, and whole body metabolism in female C57BL/6J mice. Our results show that GSK3 content is higher in the female soleus versus the male soleus; however, there were no differences in the extensor digitorum longus (EDL). Furthermore, muscle-specific GSK3 knockdown did not alter body composition in female mice, nor did it alter daily energy expenditure, glucose/insulin tolerance, mitochondrial respiration, or the expression of the SERCA uncouplers sarcolipin and neuronatin. We also did not find any differences in soleus muscle size, strength, or fatigue resistance. In the EDL, we found that an increase in absolute and specific force production, but there were no differences in fatigability. Therefore, our study highlights sex differences in the response to genetic reduction of gsk3, with most of the effects previously observed in male mice being absent in females.NEW & NOTEWORTHY Here we show that partial GSK3 knockdown has minimal effects on whole body metabolism and muscle contractility in female mice. This is partly inconsistent with previous results found in male mice, which reveal a potential influence of biological sex.

Carnosic Acid against Lung Cancer: Induction of Autophagy and Activation of Sestrin-2/LKB1/AMPK Signalling.

Non-small cell lung cancer (NSCLC) represents 80% of all lung cancer cases and is characterized by low survival rates due to chemotherapy and radiation resistance. Novel treatment strategies for NSCLC are urgently needed. Liver kinase B1 (LKB1), a tumor suppressor prevalently mutated in NSCLC, activates AMP-activated protein kinase (AMPK) which in turn inhibits mammalian target of rapamycin complex 1 (mTORC1) and activates unc-51 like autophagy activating kinase 1 (ULK1) to promote autophagy. Sestrin-2 is a stress-induced protein that enhances LKB1-dependent activation of AMPK, functioning as a tumor suppressor in NSCLC. In previous studies, rosemary (Rosmarinus officinalis) extract (RE) activated the AMPK pathway while inhibiting mTORC1 to suppress proliferation, survival, and migration, leading to the apoptosis of NSCLC cells. In the present study, we investigated the anticancer potential of carnosic acid (CA), a bioactive polyphenolic diterpene compound found in RE. The treatment of H1299 and H460 NSCLC cells with CA resulted in concentration and time-dependent inhibition of cell proliferation assessed with crystal violet staining and 3H-thymidine incorporation, and concentration-dependent inhibition of survival, assessed using a colony formation assay. Additionally, CA induced apoptosis of H1299 cells as indicated by decreased B-cell lymphoma 2 (Bcl-2) levels, increased cleaved caspase-3, -7, poly (ADP-ribose) polymerase (PARP), Bcl-2-associated X protein (BAX) levels, and increased nuclear condensation. These antiproliferative and proapoptotic effects coincided with the upregulation of sestrin-2 and the phosphorylation/activation of LKB1 and AMPK. Downstream of AMPK signaling, CA increased levels of autophagy marker light chain 3 (LC3), an established marker of autophagy; inhibiting autophagy with 3-methyladenine (3MA) blocked the antiproliferative effect of CA. Overall, these data indicate that CA can inhibit NSCLC cell viability and that the underlying mechanism of action of CA involves the induction of autophagy through a Sestrin-2/LKB1/AMPK signaling cascade. Future experiments will use siRNA and small molecule inhibitors to better elucidate the role of these signaling molecules in the mechanism of action of CA as well as tumor xenograft models to assess the anticancer properties of CA in vivo.

Celebrating a decade of exercise physiology and metabolism research in physiological reports.

During its first decade of life, Physiological Reports has become a home for well-conceived and rigorously performed exercise physiology and metabolism studies. The breadth of research within this area is impressive, covering exercise-induced increases in skeletal muscle gene expression to the effects of exercise on the gut microbiome. The purpose of the current review is to highlight some of the impactful exercise physiology and metabolism papers published in the journal and to look ahead to what areas exercise physiology publications might address in the next 10 years.

Brain atrophy, reduced cerebral perfusion, arterial stiffening, and wall thickening with aging coincide with stimulus-specific changes in fMRI-BOLD responses.

The aim of this study was to investigate how aging affects blood flow and structure of the brain. It was hypothesized older individuals would have lower gray matter volume (GMV), resting cerebral blood flow (CBF0), and depressed responses to isometabolic and neurometabolic stimuli. In addition, increased carotid-femoral pulse-wave velocity (PWV), carotid intima-media thickness (IMT), and decreased brachial flow-mediated dilation (FMD) would be associated with lower CBF0, cerebrovascular reactivity (CVR), and GMV. Brain scans (magnetic resonance imaging) and cardiovascular examinations were conducted in young (age = 24 ± 3 yr, range = 22-28 yr; n = 13) and old (age = 71 ± 4 yr; range = 67-82 yr, n = 14) participants, and CBF0, CVR [isometabolic % blood oxygen level-dependent (BOLD) in response to a breath hold (BH)], brain activation patterns during a working memory task (neurometabolic %BOLD response to N-back trial), GMV, PWV, IMT, and FMD were measured. CBF0 and to a lesser extent CVRBH were lower in the old group (P ≤ 0.050); however, the increase in the %BOLD response to the memory task was not blunted (P ≥ 0.2867). Age-related differential activation patterns during the working memory task were characterized by disinhibition of the default mode network in the old group (P < 0.0001). Linear regression analyses revealed PWV, and IMT were negatively correlated with CBF0, CVRBH, and GMV across age groups, but within the old group alone only the relationships between PWV-CVRBH and IMT-GMV remained significant (P ≤ 0.0183). These findings suggest the impacts of age on cerebral %BOLD responses are stimulus specific, brain aging involves alterations in cerebrovascular and possibly neurocognitive control, and arterial stiffening and wall thickening may serve a role in cerebrovascular aging.NEW & NOTEWORTHY Cerebral perfusion was lower in old versus young adults. %Blood oxygen level-dependent (BOLD) responses to an isometabolic stimulus and gray matter volume were decreased in old versus young adults and associated with arterial stiffening and wall thickening. The increased %BOLD response to a neurometabolic stimulus appeared unaffected by age; however, the old group displayed disinhibition of the default mode network during the stimulus. Thus, age-related alterations in cerebral %BOLD responses were stimulus specific and related to arterial remodeling.

Influence of metabolic stress and metformin on synaptic protein profile in SH-SY5Y-derived neurons.

Insulin resistance (IR) is associated with reductions in neuronal proteins often observed with Alzheimer's disease (AD), however, the mechanisms through which IR promotes neurodegeneration/AD pathogenesis are poorly understood. Metformin (MET), a potent activator of the metabolic regulator AMPK is used to treat IR but its effectiveness for AD is unclear. We have previously shown that chronic AMPK activation impairs neurite growth and protein synthesis in SH-SY5Y neurons, however, AMPK activation in IR was not explored. Therefore, we examined the effects of MET-driven AMPK activation with and without IR. Retinoic acid-differentiated SH-SY5Y neurons were treated with: (1) Ctl: 24 h vehicle followed by 24 h Vehicle; (2) HI: 100 nM insulin (24 h HI followed by 24 h HI); or (3) MET: 24 h vehicle followed by 24 h 2 mM metformin; (4) HI/MET: 24 h 100 nM insulin followed by 24 h 100 nM INS+2 mM MET. INS and INS/MET groups saw impairments in markers of insulin signaling (Akt S473, mTOR S2448, p70s6k T389, and IRS-1S636) demonstrating IR was not recovered with MET treatment. All treatment groups showed reductions in neuronal markers (post-synaptic marker HOMER1 mRNA content and synapse marker synaptophysin protein content). INS and MET treatments showed a reduction in the content of the mature neuronal marker NeuN that was prevented by INS/MET. Similarly, increases in cell size/area, neurite length/area observed with INS and MET, were prevented with INS/MET. These findings indicate that IR and MET impair neuronal markers through distinct pathways and suggest that MET is ineffective in treating IR-driven impairments in neurons.

Memory impairment in the D2.mdx mouse model of Duchenne muscular dystrophy is prevented by the adiponectin receptor agonist ALY688.

NEW FINDINGS: What is the central question of this study? Can adiponectin receptor agonism improve recognition memory in a mouse model of Duchenne muscular dystrophy? What is the main finding and its importance? Short-term treatment with the new adiponectin receptor agonist ALY688 improves recognition memory in D2.mdx mice. This finding suggests that further investigation into adiponectin receptor agonism is warranted, given that there remains an unmet need for clinical approaches to treat this cognitive dysfunction in people with Duchenne muscular dystrophy. ABSTRACT: Memory impairments have been well documented in people with Duchenne muscular dystrophy (DMD). However, the underlying mechanisms are poorly understood, and there is an unmet need to develop new therapies to treat this condition. Using a novel object recognition test, we show that recognition memory impairments in D2.mdx mice are completely prevented by daily treatment with the new adiponectin receptor agonist ALY688 from day 7 to 28 of age. In comparison to age-matched wild-type mice, untreated D2.mdx mice demonstrated lower hippocampal mitochondrial respiration (carbohydrate substrate), greater serum interleukin-6 cytokine content and greater hippocampal total tau and Raptor protein contents. Each of these measures was partly or fully preserved after treatment with ALY688. Collectively, these results indicate that adiponectin receptor agonism improves recognition memory in young D2.mdx mice.

Exercise training and BDNF injections alter amyloid precursor protein (APP) processing enzymes and improve cognition.

Exercise reduces cognitive aging, neurodegeneration, and Alzheimer's disease (AD) risk. Acute exercise reduces the activity of ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1), the rate-limiting enzyme in the production of Aß. However, mechanisms mediating these effects remain largely unknown. Work has implicated brain-derived neurotrophic factor (BDNF) in the processing of amyloid precursor protein (APP). BDNF is an exercise-induced neurotrophin known for its role in synaptic plasticity, neurite growth, and neuronal survival. Previously, our lab has shown using an ex vivo model that treatment of the prefrontal cortex with BDNF reduced BACE1 activity, highlighting a BDNF to BACE1 link. The purpose of this research was to examine whether BDNF treatments resulted in similar biochemical adaptations to APP processing as exercise training. Male C57BL6/J mice were assigned into one of four groups (n = 12/group): 1) control; 2) exercise training (progressive treadmill training 5 days/wk); 3) BDNF (0.5 mg/kg body mass subcutaneous injection 5 days/wk); or 4) endurance training and BDNF, for an 8-wk intervention. Recognition memory was measured with a novel object recognition test. Serum, the prefrontal cortex, and hippocampus were collected. BDNF improved recognition memory to a similar extent as endurance training. BDNF and exercise decreased BACE1 activity and increased ADAM10 activity in the prefrontal cortex, indicating a shift in APP processing. Our novel results indicate that BDNF exerts similar beneficial effects on cognition and APP processing as exercise training. Future evidence-based preventative or therapeutic interventions that increase BDNF and reduce BACE1 will be of value for populations that are at risk of AD.NEW & NOTEWORTHY Our study presents the novel findings that chronic peripheral BDNF injections result in regulation of APP processing enzymes and improved cognition to a similar extent as exercise training. These findings highlight the potential efficacy of using BDNF as a therapeutic intervention in the prevention of neurodegenerative diseases (i.e., Alzheimer's disease). Furthermore, future evidence-based preventative or therapeutic interventions that increase BDNF and reduce BACE1 will be of value for populations that are at risk of AD.

Acute interleukin-6 modulates key enzymes involved in prefrontal cortex and hippocampal amyloid precursor protein processing.

Exercise has been shown to be beneficial for individuals with Alzheimer's disease (AD). In rodent models of AD, exercise decreases the amyloidogenic processing of the amyloid precursor protein (APP). Although it remains unclear as to how exercise is promoting this shift away from pathological APP processing, there is emerging evidence that exercise-induced factors released from peripheral tissues may facilitate these alterations in brain APP processing. Interleukin-6 (IL-6) is released from multiple organs into peripheral circulation during exercise and is among the most characterized exerkines. The purpose of this study is to examine whether acute IL-6 can modulate key enzymes responsible for APP processing, namely, a disintegrin and metalloproteinase 10 (ADAM10) and ß-site amyloid precursor protein-cleaving enzyme 1 (BACE1), which initiate the nonamyloidogenic and amyloidogenic cascades, respectively. Male 10-wk-old C57BL/6J mice underwent acute treadmill exercise bout or were injected with either IL-6 or a PBS control 15 min prior to tissue collection. ADAM10 and BACE1 enzyme activity, mRNA, and protein expression, as well as downstream markers of both cascades, including soluble APPα (sAPPα) and soluble APPß (sAPPß), were examined. Exercise increased circulating IL-6 and brain IL-6 signaling (pSTAT3 and Socs3 mRNA). This occurred alongside a reduction in BACE1 activity and an increase in ADAM10 activity. IL-6 injection reduced BACE1 activity and increased sAPPα protein content in the prefrontal cortex. In the hippocampus, IL-6 injection decreased BACE1 activity and sAPPß protein content. Our results show that acute IL-6 injection increases markers of the nonamyloidogenic cascade and decreases markers of the amyloidogenic cascade in the cortex and hippocampus of the brain.NEW & NOTEWORTHY It is becoming evident that exercise modulates APP processing and can reduce amyloid-beta (Aß) peptide production. Our data help to explain this phenomenon by highlighting IL-6 as an exercise-induced factor that lowers pathological APP processing. These results also highlight brain regional differences in response to acute IL-6.

Sclerostin Influences Exercise-Induced Adaptations in Body Composition and White Adipose Tissue Morphology in Male Mice.

Sclerostin is an inhibitor of the osteogenic Wnt/ß-catenin signaling pathway that also has an endocrine role in regulating adipocyte differentiation and metabolism. Additionally, subcutaneous white adipose tissue (scWAT) sclerostin content decreases following exercise training (EXT). Therefore, we hypothesized that EXT-induced reductions in adipose tissue sclerostin may play a role in regulating adaptations in body composition and whole-body metabolism. To test this hypothesis, 10-week-old male C57BL/6J mice were either sedentary (SED) or performing 1 hour of treadmill running at ~65% to 70% maximum oxygen consumption (VO2max ) 5 day/week (EXT) for 4 weeks and had subcutaneous injections of either saline (C) or recombinant sclerostin (S) (0.1 mg/kg body mass) 5 day/week; thus, making four groups (SED-C, EXT-C, SED-S, and EXT-S; n = 12/group). No differences in body mass were observed between experimental groups, whereas food intake was higher in EXT (p = 0.03) and S (p = 0.08) groups. There was a higher resting energy expenditure in all groups compared to SED-C. EXT-C had increased lean mass and decreased fat mass percentage compared to SED-C and SED-S. No differences in body composition were observed in either the SED-S or EXT-S groups. Lower scWAT (inguinal), epididymal white adipose tissue (eWAT) (visceral epididymal) mass, and scWAT adipocyte cell size and increased percentage of multilocular cells in scWAT were observed in the EXT-C group compared to SED-C, whereas lower eWAT was only observed in the EXT-S group. EXT mice had increased scWAT low-density lipoprotein receptor-related protein 4 (Lrp4) and mitochondrial content and sclerostin treatment only inhibited increased Lrp4 content with EXT. Together, these results provide evidence that reductions in resting sclerostin with exercise training may influence associated alterations in energy metabolism and body composition, particularly in scWAT. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Beyond its Psychiatric Use: The Benefits of Low-dose Lithium Supplementation.

Lithium is most well-known for its mood-stabilizing effects in the treatment of bipolar disorder. Due to its narrow therapeutic window (0.5-1.2 mM serum concentration), there is a stigma associated with lithium treatment and the adverse effects that can occur at therapeutic doses. However, several studies have indicated that doses of lithium under the predetermined therapeutic dose used in bipolar disorder treatment may have beneficial effects not only in the brain but across the body. Currently, literature shows that low-dose lithium (≤0.5 mM) may be beneficial for cardiovascular, musculoskeletal, metabolic, and cognitive function, as well as inflammatory and antioxidant processes of the aging body. There is also some evidence of low-dose lithium exerting a similar and sometimes synergistic effect on these systems. This review summarizes these findings with a focus on low-dose lithium's potential benefits on the aging process and age-related diseases of these systems, such as cardiovascular disease, osteoporosis, sarcopenia, obesity and type 2 diabetes, Alzheimer's disease, and the chronic low-grade inflammatory state known as inflammaging. Although lithium's actions have been widely studied in the brain, the study of the potential benefits of lithium, particularly at a low dose, is still relatively novel. Therefore, this review aims to provide possible mechanistic insights for future research in this field.

Low-Dose Lithium Supplementation Influences GSK3ß Activity in a Brain Region Specific Manner in C57BL6 Male Mice.

BACKGROUND: Lithium, a commonly used treatment for bipolar disorder, has been shown to have neuroprotective effects for other conditions including Alzheimer's disease via the inhibition of the enzyme glycogen synthase kinase-3 (GSK3). However, dose-dependent adverse effects of lithium are well-documented, highlighting the need to determine if low doses of lithium can reliably reduce GSK3 activity. OBJECTIVE: The purpose of this study was to evaluate the effects of a low-dose lithium supplementation on GSK3 activity in the brain of an early, diet-induced Alzheimer's disease model. METHODS: Male C57BL/6J mice were divided into either a 6-week or 12-week study. In the 6-week study, mice were fed a chow diet or a chow diet with lithium-supplemented drinking water (10 mg/kg/day) for 6 weeks. Alternatively, in the 12-week study, mice were fed a chow diet, a high-fat diet (HFD), or a HFD with lithium-supplemented drinking water for 12 weeks. Prefrontal cortex and hippocampal tissues were collected for analysis. RESULTS: Results demonstrated reduced GSK3 activity in the prefrontal cortex as early as 6 weeks of lithium supplementation, in the absence of inhibitory phosphorylation changes. Further, lithium supplementation in an obese model reduced prefrontal cortex GSK3 activity as well as improved insulin sensitivity. CONCLUSION: Collectively, these data provide evidence for low-dose lithium supplementation to inhibit GSK3 activity in the brain. Moreover, these results indicate that GSK3 activity can be inhibited despite any changes in phosphorylation. These findings contribute to an overall greater understanding of low-dose lithium's ability to influence GSK3 activity in the brain and its potential as an Alzheimer's disease prophylactic.

Voluntary wheel running alters markers of amyloid-beta precursor protein processing in an ovarian hormone depleted model.

Introduction: Aberrant cleavage of the transmembrane protein, amyloid-beta precursor protein (ABPP), results in the overproduction of amyloid-beta (AB) peptides which can form senile plaques in the brain. These plaques can get lodged within synapses and disrupt neuronal communication ultimately leading to rampant neuron death. The rate-limiting enzyme in AB production is beta-site ABPP cleaving enzyme 1 (BACE1). In females, estrogen loss is associated with increases in AB and BACE1 content and activity. Exercise is known to have anti-amyloidogenic effects and may be able to alter BACE1 in cases of ovarian hormone depletion. This study aimed to examine the effects of physical activity on BACE1 in intact and ovariectomized female mice. Methods: Female C57BL/6 mice (24 weeks old) underwent bilateral ovariectomy (OVX; n=20) or SHAM surgery (SHAM; n=20). Mice were assigned to one of four groups (n=10/group) for 8 weeks: (1) sham (SHAM), (2) sham with a wheel (SHAM VWR), (3) ovariectomized (OVX), or (4) ovariectomized with a wheel (OVX VWR). Results: Novel object recognition testing demonstrated that OVX mice had a lower percentage of novel object investigation time compared to SHAM. OVX mice also had higher prefrontal cortex BACE1 activity compared to SHAM (p<0.0001), while the OVX+VWR activity was not different from SHAM. Discussions: Our results demonstrate that voluntary wheel running in an ovariectomized model prevented increases in BACE1 activity, maintained memory recall, and may provide a method of slowing the progression of Alzheimer's disease.

Erratum: Corringendum: The effects of neurogranin knockdown on SERCA pump efficiency in soleus muscles of female mice fed a high fat diet.

[This corrects the article DOI: 10.3389/fendo.2022.957182.].

Low-dose lithium supplementation promotes adipose tissue browning and sarco(endo)plasmic reticulum Ca2+ ATPase uncoupling in muscle.

Sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) uncoupling in skeletal muscle and mitochondrial uncoupling via uncoupling protein 1 (UCP1) in brown/beige adipose tissue are two mechanisms implicated in energy expenditure. Here, we investigated the effects of glycogen synthase kinase 3 (GSK3) inhibition via lithium chloride (LiCl) treatment on SERCA uncoupling in skeletal muscle and UCP1 expression in adipose. C2C12 and 3T3-L1 cells treated with LiCl had increased SERCA uncoupling and UCP1 protein levels, respectively, ultimately raising cellular respiration; however, this was only observed when LiCl treatment occurred throughout differentiation. In vivo, LiCl treatment (10 mg/kg/day) increased food intake in chow-fed diet and high-fat diet (HFD; 60% kcal)-fed male mice without increasing body mass-a result attributed to elevated daily energy expenditure. In soleus muscle, we determined that LiCl treatment promoted SERCA uncoupling via increased expression of SERCA uncouplers, sarcolipin and/or neuronatin, under chow-fed and HFD-fed conditions. We attribute these effects to the GSK3 inhibition observed with LiCl treatment as partial muscle-specific GSK3 knockdown produced similar effects. In adipose, LiCl treatment inhibited GSK3 in inguinal white adipose tissue (iWAT) but not in brown adipose tissue under chow-fed conditions, which led to an increase in UCP1 in iWAT and a beiging-like effect with a multilocular phenotype. We did not observe this beiging-like effect and increase in UCP1 in mice fed a HFD, as LiCl could not overcome the ensuing overactivation of GSK3. Nonetheless, our study establishes novel regulatory links between GSK3 and SERCA uncoupling in muscle and GSK3 and UCP1 and beiging in iWAT.

The effects of neurogranin knockdown on SERCA pump efficiency in soleus muscles of female mice fed a high fat diet.

The sarco(endo)plasmic reticulum Ca2+ ATPase (SERCA) pump is responsible for the transport of Ca2+ from the cytosol into the sarcoplasmic reticulum at the expense of ATP, making it a regulator of both muscle relaxation and muscle-based energy expenditure. Neurogranin (Ng) is a small protein that negatively regulates calcineurin signaling. Calcineurin is Ca2+/calmodulin dependent phosphatase that promotes the oxidative fibre type in skeletal muscle and regulates muscle-based energy expenditure. A recent study has shown that calcineurin activation reduces SERCA Ca2+ transport efficiency, ultimately raising energy expenditure. Since the biomedical view of obesity states that it arises as an imbalance between energy intake and expenditure which favors the former, we questioned whether heterozygous Ng deletion (Ng+/- ) would reduce SERCA efficiency and increase energy expenditure in female mice fed a high-fat diet (HFD). Young (3-4-month-old) female wild type (WT) and Ng+/- mice were fed a HFD for 12 weeks with their metabolic profile being analyzed using metabolic cages and DXA scanning, while soleus SERCA efficiency was measured using SERCA specific Ca2+ uptake and ATPase activity assays. Ng+/- mice showed significantly less cage ambulation compared to WT mice but this did not lead to any added weight gain nor changes in daily energy expenditure, glucose or insulin tolerance despite a similar level of food intake. Furthermore, we observed significant reductions in SERCA's apparent coupling ratio which were associated with significant reductions in SERCA1 and phospholamban content. Thus, our results show that Ng regulates SERCA pump efficiency, and future studies should further investigate the potential cellular mechanisms.