Nicotinamide riboside (NR), a natural precursor of NAD⁺, has been suggested to confer protection against metabolic and age-related disorders. However, its effect on chronic kidney disease (CKD), particularly in the context of obesity, remains poorly understood. Here, we evaluated the potential effects of NR supplementation in models of obesity-induced renal injury. The metabolic and renal effects of both preventive and interventional NR supplementation were assessed in mice fed high-fat or low-fat diets. Our data showed that NAD⁺ repletion by NR supplementation, whether preventive or interventional, did not affect body or organ weights, and did not ameliorate glucose metabolism, insulin resistance, or hepatic and renal lipid accumulation. NR supplementation was however associated with SIRT3-mediated deacetylation of SOD2 in the renal tissue of obese mice. It moderately reduced renal dysfunction and was associated with increased mitochondrial content. To further explore the cellular mechanisms underlying the renal effects of NR in a lipotoxic context, we investigated its impact on renal proximal tubular cells exposed to palmitic acid (PA). NR significantly prevented oxidative stress in proximal tubular epithelial cells, as evidenced by the activation of SOD2 as well as the reduction of lipid peroxidation. Moreover, NR improved mitochondrial damage and promoted mitophagy. However, NR did not reduce PA-induced lipid accumulation. In conclusion, this study provides evidence that NR exerts antioxidant effects and enhances mitochondrial function in renal cells in vitro but does not protect obese mice from metabolic disorders and associated CKD.

Nicotinamide riboside (NR), a natural precursor of NAD⁺, has been suggested to confer protection against metabolic and age-related disorders. However, its impact on chronic kidney disease (CKD), particularly in the context of obesity, remains poorly understood. Here, we evaluated the potential effects of NR supplementation in models of obesity-induced renal injury. The metabolic and renal effects of both preventive and interventional NR supplementation were assessed in mice fed high-fat or low-fat diets. Our data showed that NAD⁺ repletion, whether preventive or interventional, did not affect body or organ weights, glucose metabolism, insulin resistance, or hepatic and renal lipid accumulation. NR supplementation was however associated with SIRT3-mediated deacetylation of SOD2 in the renal tissue of obese mice, and it moderately reduced renal dysfunction. To further explore the cellular mechanisms underlying the renal effects of NR in a lipotoxic context, we investigated its impact on renal proximal tubular cells exposed to palmitic acid (PA). NR significantly prevented oxidative stress in proximal tubular epithelial cells, as evidenced by the activation of SOD2 and the reduction of lipid peroxidation and mitochondrial dysfunction. However, NR did not reduce PA-induced lipid accumulation. In conclusion, this study provides evidence that NR exerts antioxidant effects and enhances mitochondrial function in renal cells in vitro but does not protect obese mice from metabolic disorders and associated CKD. ### Competing Interest Statement The authors have declared no competing interest. F.R.S-FNRS (Fonds de la Recherche Scientifique), J004620F Société Francophone du Diabète, https://ror.org/05gdhxj91 NARILIS (NAmur Research Institute for LIfe Sciences, Belgium) UMONS Research Institute for Health Sciences and Technology (Belgium) FRMH (Fonds pour la Recherche Médicale dans le Hainaut, Belgium)

Disuse-mediated Muscle Atrophy (DMA) causes persistent muscle weakness, limiting exercise training as a treatment. Adiponectin (ApN) emerged as a therapeutic candidate for muscle disorders. However, the effect of DMA on the ApN pathway remains poorly studied. Given ApN's metabolic effects, examining the ApN pathway response to disuse in relation with muscle type is essential. To mimic DMA while avoiding confounding factors, we combined HindLimb Unloading with Immobilization (HLUI) through a device allowing mouse displacements. The effects of disuse on DMA severity were studied in the slow-twitch Soleus and the fast-twitch Tibialis anterior (TA) muscles, together with the ApN pathway. The Soleus muscle presents a moderate atrophy of type IIa myofibers, whereas the TA muscle is more severely affected and exhibits a type I to IIa switch. HLUI increased the hybrid I/IIa myofiber proportion in both muscles, suggesting an ongoing myofiber switch that is delayed in the Soleus muscle. Concomitantly, HLUI enhances ApN plasma level, modifies oligomeric form proportions, and downregulates Adiporeceptors in the Soleus but not in the TA muscle. In conclusion, HLUI is associated with a higher ApN plasma level and disturbances in oligomeric form proportions. DMA severity, myofiber switch kinetics, and adiporeceptor regulation are muscle-type dependent.

FacioScapuloHumeral muscular Dystrophy (FSHD) is one of the most prevalent inherited muscle disorders and is linked to the inappropriate expression of the DUX4 transcription factor in skeletal muscles. The deregulated molecular network causing FSHD muscle dysfunction and pathology is not well understood. It has been shown that the hypoxia response factor HIF1α is critically disturbed in FSHD and has a major role in DUX4-induced cell death. In this study, we further explored the relationship between DUX4 and HIF1α. We found that the DUX4 and HIF1α link differed according to the stage of myogenic differentiation and was conserved between human and mouse muscle. Furthermore, we found that HIF1α knockdown in a mouse model of DUX4 local expression exacerbated DUX4-mediated muscle fibrosis. Our data indicate that the suggested role of HIF1α in DUX4 toxicity is complex and that targeting HIF1α might be challenging in the context of FSHD therapeutic approaches.

Renal proximal tubules are a primary site of injury in metabolic diseases. In obese patients and animal models, proximal tubular epithelial cells (PTECs) display dysregulated lipid metabolism, organelle dysfunctions, and oxidative stress that contribute to interstitial inflammation, fibrosis and ultimately end-stage renal failure. Our research group previously pointed out AMP-activated protein kinase (AMPK) decline as a driver of obesity-induced renal disease. Because PTECs display high macroautophagic/autophagic activity and rely heavily on their endo-lysosomal system, we investigated the effect of lipid stress on autophagic flux and lysosomes in these cells. Using a model of highly differentiated primary PTECs challenged with palmitate, our data placed lysosomes at the cornerstone of the lipotoxic phenotype. As soon as 6 h after palmitate exposure, cells displayed impaired lysosomal acidification subsequently leading to autophagosome accumulation and activation of lysosomal biogenesis. We also showed the inability of lysosomal quality control to restore acidic pH which finally drove PTECs dedifferentiation. When palmitate-induced AMPK activity decline was prevented by AMPK activators, lysosomal acidification and the differentiation profile of PTECs were preserved. Our work provided key insights on the importance of lysosomes in PTECs homeostasis and lipotoxicity and demonstrated the potential of AMPK in protecting the organelle from lipid stress.Abbreviation: ACAC: acetyl-CoA carboxylase; ACTB: actin beta; AICAR: 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside; AMPK: AMP-activated protein kinase; APQ1: aquaporin 1 (Colton blood group); BSA: bovine serum albumin; CDH16: cadherin 16; CKD: chronic kidney disease; CTSB: cathepsin B; CTSD: cathepsin D; EPB41L5: erythrocyte membrane protein band 4.1 like 5; EIF4EBP1: eukaryotic translation initiation factor 4E binding protein 1; EMT: epithelial-to-mesenchymal transition; FA: fatty acid; FCCP: carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone; GFP: green fluorescent protein; GUSB: glucuronidase beta; HEXB: hexosaminidase subunit beta; LAMP: lysosomal associated membrane protein; LD: lipid droplet; LGALS3: galectin 3; LLOMe: L-leucyl-L-leucine methyl ester hydrobromide; LMP: lysosomal membrane permeabilization; LRP2: LDL receptor related protein 2; LSD: lysosomal storage disorder; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MCOLN1: mucolipin TRP cation channel 1; MG132: N-benzyloxycarbonyl-L-leucyl-L-leucyl-L-leucinal; MmPTECs: Mus musculus (mouse) proximal tubular epithelial cells; MTORC1: mechanistic target of rapamycin kinase complex 1; OA: oleate; PA: palmitate; PIKFYVE: phosphoinositide kinase, FYVE-type zinc finger containing; PTs: proximal tubules; PTECs: proximal tubular epithelial cells; PRKAA: protein kinase AMP-activated catalytic subunit alpha; RFP: red fluorescent protein; RPS6KB: ribosomal protein S6 kinase B; SLC5A2: solute carrier family 5 member 2; SOX9: SRY-box transcription factor 9; SQSTM1: sequestosome 1; TFEB: transcription factor EB; Ub: ubiquitin; ULK1: unc-51 like autophagy activating kinase 1; VIM: vimentin

Although non-alcoholic fatty liver disease (NAFLD) presents as an intricate condition characterized by a growing prevalence, the often-recommended lifestyle interventions mostly lack high-level evidence of efficacy and there are currently no effective drugs proposed for this indication. The present review delves into NAFLD pathology, its diverse underlying physiopathological mechanisms and the available in vitro, in vivo, and clinical evidence regarding the use of natural compounds for its management, through three pivotal targets (oxidative stress, cellular inflammation, and insulin resistance). The promising perspectives that natural compounds offer for NAFLD management underscore the need for additional clinical and lifestyle intervention trials. Encouraging further research will contribute to establishing more robust evidence and practical recommendations tailored to patients with varying NAFLD grades.

Kidney diseases, including chronic kidney disease (CKD), diabetic nephropathy, and acute kidney injury (AKI), represent a significant global health burden. The kidneys are metabolically very active organs demanding a large amount of ATP. They are composed of highly specialized cell types in the glomerulus and subsequent tubular compartments which fine-tune metabolism to meet their numerous and diverse functions. Defective renal cell metabolism, including altered fatty acid oxidation or glycolysis, has been linked to both AKI and CKD. Mitochondria play a vital role in renal metabolism, and emerging research has identified mitochondrial sirtuins (SIRT3, SIRT4 and SIRT5) as key regulators of renal cell metabolic adaptation, especially SIRT3. Sirtuins belong to an evolutionarily conserved family of mainly NAD+-dependent deacetylases, deacylases, and ADP-ribosyl transferases. Their dependence on NAD+, used as a co-substrate, directly links their enzymatic activity to the metabolic status of the cell. In the kidney, SIRT3 has been described to play crucial roles in the regulation of mitochondrial function, and the antioxidative and antifibrotic response. SIRT3 has been found to be constantly downregulated in renal diseases. Genetic or pharmacologic upregulation of SIRT3 has also been associated with beneficial renal outcomes. Importantly, experimental pieces of evidence suggest that SIRT3 may act as an important energy sensor in renal cells by regulating the activity of key enzymes involved in metabolic adaptation. Activation of SIRT3 may thus represent an interesting strategy to ameliorate renal cell energetics. In this review, we discuss the roles of SIRT3 in lipid and glucose metabolism and in mediating a metabolic switch in a physiological and pathological context. Moreover, we highlight the emerging significance of other mitochondrial sirtuins, SIRT4 and SIRT5, in renal metabolism. Understanding the role of mitochondrial sirtuins in kidney diseases may also open new avenues for innovative and efficient therapeutic interventions and ultimately improve the management of renal injuries.

Introduction: COVID-19 vaccine was demonstrated to be effective in dialysis patients, but boosters are mandatory due to a rapid waning of anti-spike antibodies. A vaccination strategy based on immunologic response might be useful to maintain a favorable risk-benefit balance in this vulnerable population. Methods: CoviDial is an observational prospective study enrolling 121 dialysis patients to receive a 3-dose mRNA-1273 vaccine according to a uniform schedule. At baseline, months 1, 3, 6, 9, and 12, anti-spike antibodies against four epitopes (S1, S2, ECD-S1 + S2, RBD) were monitored with a multiplex immunodot enzymatic assay. Potential correlation between initial serologic response and subsequent COVID-19 infection was then assessed. Results: Overall, 96.2% and 96.8% of patients had anti-RBD antibodies at 3 and 12 months, respectively. All antibodies titers significantly decreased at month 6 compared to month 3. Booster vaccine induced a robust serologic response at month 9, but with a waning 3 months later, particularly for anti-S2 (37.2 +/- 3.3 vs. 61.3 +/- 3.0, p < 0.0001) and anti-S1 + S2 antibodies (68.4 +/- 3.3 vs. 88.4 +/- 2.3, p = 0.0015). Fifteen patients were later tested positive for SARS-CoV-2. At month 3, mean titers of anti-RBD, anti-S1 + S2, and anti-S2 antibodies were lower in the subsequent SARS-CoV-2 infected cohort (71.57 +/- 9.01 vs. 85.79 +/- 2.61, p = 0.0131; 41.07 +/- 7.96 vs. 61.68 +/- 3.56, p = 0.0237; 13.79 +/- 5.03 vs. 39.70 +/- 3.86, p = 0.0096; respectively). Conclusion: Three doses of mRNA-1273 vaccine induce a robust but time-limited immunologic response in dialysis patients. Lower anti-spike antibodies titers after initial vaccination are associated with a higher risk to subsequently contract SARS-CoV-2, even beyond 6 months.

Sex differences have been observed in the development of obesity-related complications in patients, as well as in animal models. Accumulating evidence suggests that sex-dependent regulation of lipid metabolism contributes to sex-specific physiopathology. Lipid accumulation in the renal tissue has been shown to play a major role in the pathogenesis of obesity-induced kidney injury. Unlike in males, the physiopathology of the disease has been poorly described in females, particularly regarding the lipid metabolism adaptation. Here, we compared the lipid profile changes in the kidneys of female and male mice fed a high-fat diet (HFD) or low-fat diet (LFD) by lipidomics and correlated them with pathophysiological changes. We showed that HFD-fed female mice were protected from insulin resistance and hepatic steatosis compared to males, despite similar body weight gains. Females were particularly protected from renal dysfunction, oxidative stress, and tubular lipid accumulation. Both HFD-fed male and female mice presented dyslipidemia, but lipidomic analysis highlighted differential renal lipid profiles. While both sexes presented similar neutral lipid accumulation with obesity, only males showed increased levels of ceramides and phospholipids. Remarkably, protection against renal lipotoxicity in females was associated with enhanced renal adiponectin and AMP-activated protein kinase (AMPK) signaling. Circulating adiponectin and its renal receptor levels were significantly lower in obese males, but were maintained in females. This observation correlated with the maintained basal AMPK activity in obese female mice compared to males. Collectively, our findings suggest that female mice are protected from obesity-induced renal dysfunction and lipotoxicity associated with enhanced adiponectin and AMPK signaling compared to males. Obesity-related complications can differ between men and women due to sex-specific differences in how fats are handled. Here, we studied the effects of high-fat diet on the kidneys of male and female mice. We found that despite gaining similar weight, obese female mice were better protected against insulin resistance, liver fat accumulation, and kidney damage caused by obesity than males. In particular, female mice were protected against lipid accumulation in the kidneys. We further analyzed the lipid profile in the kidneys of both male and female mice and observed differences in the amount and nature of the accumulated lipids. Male mice had increased levels of specific lipids, which may contribute to their higher risk of kidney damage. In contrast, female mice showed better lipid metabolism adaptation, which helped to protect their kidneys. This study also revealed an association between higher levels of the protein hormone adiponectin and higher activity of the cellular energy master regulator protein AMPK in obese females. These proteins may help prevent obesity-induced kidney damage. In obese males, these protective proteins are reduced and are associated with kidney damage. In conclusion, this study suggests that female mice are naturally shielded from obesity-induced kidney damage and lipid accumulation in the kidneys. Obesity in males is associated with the presence of potentially toxic lipids and dysregulated renal metabolism. Understanding these sex-related differences in obesity-related complications could lead to better management and treatment of kidney problems in both men and women.

Background We have previously demonstrated that double homeobox 4 centromeric ( DUX4C ) encoded for a functional DUX4c protein upregulated in dystrophic skeletal muscles. Based on gain- and loss-of-function studies we have proposed DUX4c involvement in muscle regeneration. Here, we provide further evidence for such a role in skeletal muscles from patients affected with facioscapulohumeral muscular dystrophy (FSHD). Methods DUX4c was studied at RNA and protein levels in FSHD muscle cell cultures and biopsies. Its protein partners were co-purified and identified by mass spectrometry. Endogenous DUX4c was detected in FSHD muscle sections with either its partners or regeneration markers using co-immunofluorescence or in situ proximity ligation assay. Results We identified new alternatively spliced DUX4C transcripts and confirmed DUX4c immunodetection in rare FSHD muscle cells in primary culture. DUX4c was detected in nuclei, cytoplasm or at cell–cell contacts between myocytes and interacted sporadically with specific RNA-binding proteins involved, a.o., in muscle differentiation, repair, and mass maintenance. In FSHD muscle sections, DUX4c was found in fibers with unusual shape or central/delocalized nuclei (a regeneration feature) staining for developmental myosin heavy chain, MYOD or presenting intense desmin labeling. Some couples of myocytes/fibers locally exhibited peripheral DUX4c-positive areas that were very close to each other, but in distinct cells. MYOD or intense desmin staining at these locations suggested an imminent muscle cell fusion. We further demonstrated DUX4c interaction with its major protein partner, C1qBP, inside myocytes/myofibers that presented features of regeneration. On adjacent muscle sections, we could unexpectedly detect DUX4 (the FSHD causal protein) and its interaction with C1qBP in fusing myocytes/fibers. Conclusions DUX4c upregulation in FSHD muscles suggests it contributes not only to the pathology but also, based on its protein partners and specific markers, to attempts at muscle regeneration. The presence of both DUX4 and DUX4c in regenerating FSHD muscle cells suggests DUX4 could compete with normal DUX4c functions, thus explaining why skeletal muscle is particularly sensitive to DUX4 toxicity. Caution should be exerted with therapeutic agents aiming for DUX4 suppression because they might also repress the highly similar DUX4c and interfere with its physiological role. Graphical Abstract

Background Hypoxia is known to modify skeletal muscle biological functions and muscle regeneration. However, the mechanisms underlying the effects of hypoxia on human myoblast differentiation remain unclear. The hypoxic response pathway is of particular interest in patients with hereditary muscular dystrophies since many present respiratory impairment and muscle regeneration defects. For example, an altered hypoxia response characterizes the muscles of patients with facioscapulohumeral dystrophy (FSHD). Methods We examined the impact of hypoxia on the differentiation of human immortalized myoblasts (LHCN-M2) cultured in normoxia (PO 2 : 21%) or hypoxia (PO 2 : 1%). Cells were grown in proliferation (myoblasts) or differentiation medium for 2 (myocytes) or 4 days (myotubes). We evaluated proliferation rate by EdU incorporation, used myogenin-positive nuclei as a differentiation marker for myocytes, and determined the fusion index and myosin heavy chain-positive area in myotubes. The contribution of HIF1α was studied by gain (CoCl 2 ) and loss (siRNAs) of function experiments. We further examined hypoxia in LHCN-M2-iDUX4 myoblasts with inducible expression of DUX4, the transcription factor underlying FSHD pathology. Results We found that the hypoxic response did not impact myoblast proliferation but activated precocious myogenic differentiation and that HIF1α was critical for this process. Hypoxia also enhanced the late differentiation of human myocytes, but in an HIF1α-independent manner. Interestingly, the impact of hypoxia on muscle cell proliferation was influenced by dexamethasone. In the FSHD pathological context, DUX4 suppressed HIF1α-mediated precocious muscle differentiation. Conclusion Hypoxia stimulates myogenic differentiation in healthy myoblasts, with HIF1α-dependent early steps. In FSHD, DUX4-HIF1α interplay indicates a novel mechanism by which DUX4 could interfere with HIF1α function in the myogenic program and therefore with FSHD muscle performance and regeneration.

Aristolochic acid nephropathy (AAN) is a progressive tubulointerstitial nephritis caused by the intake of aristolochic acids (AA) contained in Chinese herbal remedies or contaminated food. AAN is characterized by tubular atrophy and interstitial fibrosis, characterizing advanced kidney disease. It is established that sustained or recurrent acute kidney injury (AKI) episodes contribute to the progression of CKD. Therefore, the study of underlying mechanisms of AA-induced nephrotoxicity could be useful in understanding the complex AKI-to-CKD transition. We developed a translational approach of AKI-to-CKD transition by reproducing human AAN in rodent models. Indeed, in such models, an early phase of acute tubular necrosis was rapidly followed by a massive interstitial recruitment of activated monocytes/macrophages followed by cytotoxic T lymphocytes, resulting in a transient AKI episode. A later chronic phase was then observed with progressive tubular atrophy related to dedifferentiation and necrosis of tubular epithelial cells. The accumulation of vimentin and αSMA-positive cells expressing TGFβ in interstitial areas suggested an increase in resident fibroblasts and their activation into myofibroblasts resulting in collagen deposition and CKD. In addition, we identified 4 major actors in the AKI-to-CKD transition: (1) the tubular epithelial cells, (2) the endothelial cells of the interstitial capillary network, (3) the inflammatory infiltrate, and (4) the myofibroblasts. This review provides the most comprehensive and informative data we were able to collect and examines the pending questions.

Proprotein convertase substilisin/kexin 9 (PCSK9) inhibitors (PCSK9i) revolutionised the lipid-lowering therapy. However, a risk of type 2 diabetes mellitus (T2DM) is evoked under PCSK9i therapy. In this review, we summarise the current knowledge on the link of PCSK9 with T2DM. A significant correlation was found between PCSK9 and insulin, homeostasis model assessment (HOMA) of insulin resistance and glycated haemoglobin. PCSK9 is also involved in inflammation. PCSK9 loss-of-function variants increased T2DM risk by altering insulin secretion. Local pancreatic low PCSK9 regulates β-cell LDLR expression which in turn promotes intracellular cholesterol accumulation and hampers insulin secretion. Nevertheless, the association of PCSK9 loss-of-function variants and T2DM is inconsistent. InsLeu and R46L polymorphisms were associated with T2DM, low HOMA for β-cell function and impaired fasting glucose, while the C679X polymorphism was associated with low fasting glucose in Black South African people. Hence, we assume that the impact of these variants on glucose homeostasis may vary depending on the genetic background of the studied populations and the type of effect caused by those genetic variants on the PCSK9 protein. Accordingly, these factors should be considered when choosing a genetic variant of PCSK9 to assess the impact of long-term use of PCSK9i on glucose homeostasis.

Facioscapulohumeral muscular dystrophy (FSHD) is characterised by descending skeletal muscle weakness and wasting. FSHD is caused by mis-expression of the transcription factor DUX4, which is linked to oxidative stress, a condition especially detrimental to skeletal muscle with its high metabolic activity and energy demands. Oxidative damage characterises FSHD and recent work suggests metabolic dysfunction and perturbed hypoxia signalling as novel pathomechanisms. However, redox biology of FSHD remains poorly understood, and integrating the complex dynamics of DUX4-induced metabolic changes is lacking. Here we pinpoint the kinetic involvement of altered mitochondrial ROS metabolism and impaired mitochondrial function in aetiology of oxidative stress in FSHD. Transcriptomic analysis in FSHD muscle biopsies reveals strong enrichment for pathways involved in mitochondrial complex I assembly, nitrogen metabolism, oxidative stress response and hypoxia signalling. We found elevated mitochondrial ROS (mitoROS) levels correlate with increases in steady-state mitochondrial membrane potential in FSHD myogenic cells. DUX4 triggers mitochondrial membrane polarisation prior to oxidative stress generation and apoptosis through mitoROS, and affects mitochondrial health through lipid peroxidation. We identify complex I as the primary target for DUX4-induced mitochondrial dysfunction, with strong correlation between complex I-linked respiration and cellular oxygenation/hypoxia signalling activity in environmental hypoxia. Thus, FSHD myogenesis is uniquely susceptible to hypoxia-induced oxidative stress as a consequence of metabolic mis-adaptation. Importantly, mitochondria-targeted antioxidants rescue FSHD pathology more effectively than conventional antioxidants, highlighting the central involvement of disturbed mitochondrial ROS metabolism. This work provides a pathomechanistic model by which DUX4-induced changes in oxidative metabolism impair muscle function in FSHD, amplified when metabolic adaptation to varying O2 tension is required.

(1) Background: White adipose tissue (WAT) is a dynamic and plastic tissue showing high sensitivity to carbohydrate supply. In such a context, the WAT may accordingly modulate its mitochondrial metabolic activity. We previously demonstrated that a partial replacement of glucose by galactose in a culture medium of 3T3-L1 cells leads to a poorer adipogenic yield and improved global mitochondrial health. In the present study, we investigate key mitochondrial metabolic actors reflecting mitochondrial adaptation in response to different carbohydrate supplies. (2) Methods: The metabolome of 3T3-L1 cells was investigated during the differentiation process using different glucose/galactose ratios and by a targeted approach using 1H-NMR (Proton nuclear magnetic resonance) spectroscopy; (3) Results: Our findings indicate a reduction of adipogenic and metabolic overload markers under the low glucose/galactose condition. In addition, a remodeling of the mitochondrial function triggers the secretion of metabolites with signaling and systemic energetical homeostasis functions. Finally, this study also sheds light on a new way to consider the mitochondrial metabolic function by considering noncarbohydrates related pathways reflecting both healthier cellular and mitochondrial adaptation mechanisms; (4) Conclusions: Different carbohydrates supplies induce deep mitochondrial metabolic and function adaptations leading to overall adipocytes function and profile remodeling during the adipogenesis.

Exercise training is now recognized as an interesting therapeutic strategy in managing obesity and its related disorders. However, there is still a lack of knowledge about its impact on obesity-induced chronic kidney disease (CKD). Here, we investigated the effects of a delayed protocol of endurance exercise training (EET) as well as the underlying mechanism in obese mice presenting CKD. Mice fed a high-fat diet (HFD) or a low-fat diet (LFD) for 12 weeks were subsequently submitted to an 8-weeks EET protocol. Delayed treatment with EET in obese mice prevented body weight gain associated with a reduced calorie intake. EET intervention counteracted obesity-related disorders including glucose intolerance, insulin resistance, dyslipidaemia and hepatic steatosis. Moreover, our data demonstrated for the first time the beneficial effects of EET on obesity-induced CKD as evidenced by an improvement of obesity-related glomerulopathy, tubulo-interstitial fibrosis, inflammation and oxidative stress. EET also prevented renal lipid depositions in the proximal tubule. These results were associated with an improvement of the AMPK pathway by EET in renal tissue. AMPK-mediated phosphorylation of ACC and ULK-1 were particularly enhanced leading to increased fatty acid oxidation and autophagy improvement with EET in obese mice.

Muscular dystrophies (MDs) are a group of inherited degenerative muscle disorders characterized by a progressive skeletal muscle wasting. Respiratory impairments and subsequent hypoxemia are encountered in a significant subgroup of patients in almost all MD forms. In response to hypoxic stress, compensatory mechanisms are activated especially through Hypoxia-Inducible Factor 1 α (HIF-1α). In healthy muscle, hypoxia and HIF-1α activation are known to affect oxidative stress balance and metabolism. Recent evidence has also highlighted HIF-1α as a regulator of myogenesis and satellite cell function. However, the impact of HIF-1α pathway modifications in MDs remains to be investigated. Multifactorial pathological mechanisms could lead to HIF-1α activation in patient skeletal muscles. In addition to the genetic defect per se, respiratory failure or blood vessel alterations could modify hypoxia response pathways. Here, we will discuss the current knowledge about the hypoxia response pathway alterations in MDs and address whether such changes could influence MD pathophysiology.