Resveratrol impinges on retrograde communication without inducing mitochondrial biogenesis in aged rat soleus muscle.

The natural polyphenol resveratrol (RSV) might counteract the skeletal muscle age-related loss of muscle mass and strength/function partly acting on mitochondria. This work analysed the effects of a six-week administration of RSV (50 mg/kg/day) in the oxidative Soleus (Sol) skeletal muscle of old rats (27 months old). RSV effects on key mitochondrial biogenesis proteins led to un unchanged amount of SIRT1 protein and a marked decrease (60 %) in PGC-1α protein. In addition, Peroxyredoxin 3 (PRXIII) protein decreased by 50 %, which on overall suggested the absence of induction of mitochondrial biogenesis by RSV in old Sol. A novel direct correlation between PGC-1α and PRXIII proteins was demonstrated by correlation analysis in RSV and ad-libitum (AL) rats, supporting the reciprocally coordinated expression of the proteins. RSV supplementation led to an unexpected 50 % increase in the frequency of the oxidized base OH8dG in mtDNA. Furthermore, RSV supplementation induced a 50 % increase in the DRP1 protein of mitochondrial dynamics. In both rat groups an inverse correlation between PGC-1α and the frequency of OH8dG as well as an inverse correlation between PRXIII and the frequency of OH8dG were also found, suggestive of a relationship between oxidative damage to mtDNA and mitochondrial biogenesis activity. Such results may indicate that the antioxidant activity of RSV in aged Sol impinged on the oxidative fiber-specific, ROS-mediated, retrograde communication, thereby affecting the expression of SIRT1, PGC-1α and PRXIII, reducing the compensatory responses to the age-related mitochondrial oxidative stress and decline.

Different Effects of High-Fat/High-Sucrose and High-Fructose Diets on Advanced Glycation End-Product Accumulation and on Mitochondrial Involvement in Heart and Skeletal Muscle in Mice.

Diets with an elevated content of fat, sucrose, or fructose are recognized models of diet-induced metabolic alterations, since they induce metabolic derangements, oxidative stress, and chronic low-grade inflammation associated with local and systemic accumulation of advanced glycation end-products (AGEs). This study used four-week-old C57BL/6 male mice, randomly assigned to three experimental dietary regimens: standard diet (SD), high-fat high-sucrose diet (HFHS), or high fructose diet (HFr), administered for 12 weeks. Plasma, heart, and tibialis anterior (TA) skeletal muscle were assayed for markers of metabolic conditions, inflammation, presence of AGEs, and mitochondrial involvement. The HFHS diet induced a tissue-specific differential response featuring (1) a remarkable adaptation of the heart to HFHS-induced heavy oxidative stress, demonstrated by an increased presence of AGEs and reduced mitochondrial biogenesis, and efficaciously counteracted by a conspicuous increase in mitochondrial fission and PRXIII expression; (2) the absence of TA adaptation to HFHS, revealed by a heavy reduction in mitochondrial biogenesis, not counteracted by an increase in fission and PRXIII expression. HFr-induced mild oxidative stress elicited tissue-specific responses, featuring (1) a decrease in mitochondrial biogenesis in the heart, likely counteracted by a tendency for increased fission and (2) a mild reduction in mitochondrial biogenesis in TA, likely counteracted by a tendency for increased fusion, showing the adaptability of both tissues to the diet.

Mitochondria Deregulations in Cancer Offer Several Potential Targets of Therapeutic Interventions.

Mitochondria play a key role in cancer and their involvement is not limited to the production of ATP only. Mitochondria also produce reactive oxygen species and building blocks to sustain rapid cell proliferation; thus, the deregulation of mitochondrial function is associated with cancer disease development and progression. In cancer cells, a metabolic reprogramming takes place through a different modulation of the mitochondrial metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, the Krebs cycle, glutamine and heme metabolism. Alterations of mitochondrial homeostasis, in particular, of mitochondrial biogenesis, mitophagy, dynamics, redox balance, and protein homeostasis, were also observed in cancer cells. The use of drugs acting on mitochondrial destabilization may represent a promising therapeutic approach in tumors in which mitochondrial respiration is the predominant energy source. In this review, we summarize the main mitochondrial features and metabolic pathways altered in cancer cells, moreover, we present the best known drugs that, by acting on mitochondrial homeostasis and metabolic pathways, may induce mitochondrial alterations and cancer cell death. In addition, new strategies that induce mitochondrial damage, such as photodynamic, photothermal and chemodynamic therapies, and the development of nanoformulations that specifically target drugs in mitochondria are also described. Thus, mitochondria-targeted drugs may open new frontiers to a tailored and personalized cancer therapy.

Targeting mitochondrial impairment for the treatment of cardiovascular diseases: From hypertension to ischemia-reperfusion injury, searching for new pharmacological targets.

Mitochondria and mitochondrial proteins represent a group of promising pharmacological target candidates in the search of new molecular targets and drugs to counteract the onset of hypertension and more in general cardiovascular diseases (CVDs). Indeed, several mitochondrial pathways result impaired in CVDs, showing ATP depletion and ROS production as common traits of cardiac tissue degeneration. Thus, targeting mitochondrial dysfunction in cardiomyocytes can represent a successful strategy to prevent heart failure. In this context, the identification of new pharmacological targets among mitochondrial proteins paves the way for the design of new selective drugs. Thanks to the advances in omics approaches, to a greater availability of mitochondrial crystallized protein structures and to the development of new computational approaches for protein 3D-modelling and drug design, it is now possible to investigate in detail impaired mitochondrial pathways in CVDs. Furthermore, it is possible to design new powerful drugs able to hit the selected pharmacological targets in a highly selective way to rescue mitochondrial dysfunction and prevent cardiac tissue degeneration. The role of mitochondrial dysfunction in the onset of CVDs appears increasingly evident, as reflected by the impairment of proteins involved in lipid peroxidation, mitochondrial dynamics, respiratory chain complexes, and membrane polarization maintenance in CVD patients. Conversely, little is known about proteins responsible for the cross-talk between mitochondria and cytoplasm in cardiomyocytes. Mitochondrial transporters of the SLC25A family, in particular, are responsible for the translocation of nucleotides (e.g., ATP), amino acids (e.g., aspartate, glutamate, ornithine), organic acids (e.g. malate and 2-oxoglutarate), and other cofactors (e.g., inorganic phosphate, NAD+, FAD, carnitine, CoA derivatives) between the mitochondrial and cytosolic compartments. Thus, mitochondrial transporters play a key role in the mitochondria-cytosol cross-talk by leading metabolic pathways such as the malate/aspartate shuttle, the carnitine shuttle, the ATP export from mitochondria, and the regulation of permeability transition pore opening. Since all these pathways are crucial for maintaining healthy cardiomyocytes, mitochondrial carriers emerge as an interesting class of new possible pharmacological targets for CVD treatments.

Surgical strategies in pediatric supracondylar humeral fractures: our experience.

BACKGROUND AND AIM: Supracondylar humeral fractures are the most common skeletal injury of childhood elbow. Treatment option for Gartland type II-III-IV fractures is based on closed reduction and percutaneous pinning (CRPP) fixation using Kirshner wires. Seldom open reduction is needed. Literature described different method of CRPP. The aim of the study is to report our experience in the surgical management of supracondylar humeral fractures comparing it with the literature, in order to identify useful information for a correct and better approach to reduce complications and improve clinical outcomes. METHODS: 148 patients with a mean age of 5.72 ± 2.52 years and with Gartland type II-III-IV humeral supracondylar fractures were treated with CRPP at our Orthopedic Pediatric Unit. They were divided into three groups according to surgical technique. Group A was represented by patients treated with cross pinning (1 medial and 1 lateral pin), Group B represented by 2 lateral pins while Group C represented by 2 lateral and one medial pin. Evaluation criteria are based on Mayo Elbow Performance Index (MEPI); Bauman's and Carrying Angle and Flynn's criteria. Data were recorded at the following times: T0 (before surgical procedure); T1 (one-month post-surgery); T2 (six months post-surgery). RESULTS: The three surgical techniques showed comparable results according to MEPI, Bauman's angle, Carrying's angle and Flynn's criteria from T0 to T1. There is an improvement for all Groups. Group C reported the best MEPI outcome at T2. However, 2 patients in this group did not show excellent results according to Flynn's criteria. CONCLUSIONS: There is no single and superior treatment for displaced humeral supracondylar fractures and that each fracture has its own personality.

Special Issue-"Orthopedics and Coronavirus: Analyze the Past to Face the Present and to Prevent the Future".

The coronavirus pandemic represented one of the most massive health emergencies in recent history [...].

Angiomatoid Fibrous Histiocytoma (AFH) of the Right Arm: An Exceptional Case with Pulmonary Metastasis and Confirmatory EWSR1::CREB1 Translocation.

Angiomatoid fibrous histiocytoma (AFH) is a rare neoplasm described for the first time by Enzinger in 1979, and classified by World Health Organization 2020 as intermediate malignant potential neoplasm. It mostly occurs in the subcutis and is characterized by varying proportions of epithelioid, ovoid and spindle cells in a nodular and syncytial growth pattern, with some hemorrhagic pseudovascular spaces. In this paper, we report the clinical case of a 62-year-old man who presented with AFH on the right arm, and relapsed three years after first surgical excision. After a further three years, the patient presented with an intramuscular localization of AFH, and 12 months after this, a pulmonary metastasis of AFH was diagnosed. Given the rarity of the spreading of AFH, we performed Fluorescence In Situ Hybridization (FISH) and we detected EWSR1::CREB1 gene fusion.

Direct Anterior versus Lateral Approach for Femoral Neck Fracture: Role in COVID-19 Disease.

Background: During the COVID-19 emergency, the incidence of fragility fractures in elderly patients remained unchanged. The management of these patients requires a multidisciplinary approach. The study aimed to assess the best surgical approach to treat COVID-19 patients with femoral neck fracture undergoing hemiarthroplasty (HA), comparing direct lateral (DL) versus direct anterior approach (DAA). Methods: A single-center, observational retrospective study including 50 patients affected by COVID-19 infection (30 males, 20 females) who underwent HA between April 2020 to April 2021 was performed. The patients were allocated into two groups according to the surgical approach used: lateral approach and anterior approach. For each patient, the data were recorded: age, sex, BMI, comorbidity, oxygen saturation (SpO2), fraction of the inspired oxygen (FiO2), type of ventilation invasive or non-invasive, HHb, P/F ratio (PaO2/FiO2), hemoglobin level the day of surgery and 1 day post operative, surgical time, Nottingham Hip Fractures Score (NHFS) and American Society of Anesthesiologists Score (ASA). The patients were observed from one hour before surgery until 48 h post-surgery of follow-up. The patients were stratified into five groups according to Alhazzani scores. A non-COVID-19 group of patients, as the control, was finally introduced. Results: A lateral position led to a better level of oxygenation (p < 0.01), compared to the supine anterior approach. We observed a better post-operative P/F ratio and a reduced need for invasive ventilation in patients lying in the lateral position. A statistically significant reduction in the surgical time emerged in patients treated with DAA (p < 0.01). Patients within the DAA group had a significantly lower blood loss compared to direct lateral approach. Conclusions: DL approach with lateral decubitus seems to preserved respiratory function in HA surgery. Thus, the lateral position may be associated with beneficial effects on gas exchange.

The effects of a new protocol on blood loss in total knee arthroplasty.

The aim of study was to evaluate the efficacy of blood loss prevention with Tranexamic acid in patients undergoing total knee arthroplasty (TKA). The Authors defined a new protocol that foresees the use of Tranexamic acid both pre-intra and post-operatively. Seventy patients indicated for TKA were enrolled. Thirty-five patients (control group) followed standard protocol without Tranexamic acid and the other 35 patients (study group) followed standard protocol with Tranexamic acid. We analyzed the values of hemoglobin (Hb), hematocrit (HCT) and red blood cells (RBCs) both pre-operatively (T0) and post-operatively: immediately after surgery (T1), at one day (T2) and three days post-op (T3). We observed statistical differences at T0 and T3 regarding the Hb, HT and RBCs value between the two groups. Moreover, 11.4% in the study and 28.5% in the control group required blood transfusion. No thrombotic or thrombo-embolic events were reported. We conclude that Tranexamic acid use, as in our protocol, reduces postoperative bleeding in primary knee arthroplasty, with the absence of thrombo-embolic events.

Plate vs reverse shoulder arthroplasty for proximal humeral fractures: The psychological health influence the choice of device?

BACKGROUND: Proximal humeral fractures represent the third most common observed osteoporotic fracture; the treatment in three and four-part proximal humeral fractures in patients over 65 years is still controversial. Among the treatments described in literature, open reduction and internal fixation (O.R.I.F) and reverse shoulder arthroplasty (RSA) are gaining an increasing popularity. AIM: To investigate the correct treatment for three and four-part proximal humeral fractures according to psychological aspects. METHODS: It was conducted a prospective study with a series of 63 patients treated with O.R.I.F. (group A) and with RSA (group B) for three and four-part proximal humeral fractures according to Neer classification system. A conservative treatment group, as control, was finally introduced. One independent observer performed clinical and a psychological evaluation at one (T0), six (T1) and twelve months (T2) postoperatively. The Constant's score and The Disabilities of the Arm, Shoulder and Hand (DASH score) were used for clinical evaluation, while General Anxiety Disorder-7 (GAD-7) and Caregiver Strain Scale (CSS) were used for psychological evaluation. RESULTS: At one month follow up in group A the mean values were DASH score 50.8, Constant score 36.1, GAD-7 score 5.4, CSS 5.0. For the group B, the average values at T0 were: DASH score 54.6, Constant score 32.0; GAD-7 score 6.4, CSS 6.2. At six months in group A the average values were DASH score 42.1, Constant score 47.3, GAD-7 score 4.3, CSS 3.9. For the group B, the average values at T1 were: DASH score 39.1, Constant score 43.2, GAD-7 score 5.7, CSS 5.5. At twelve months in the group A, the mean values were DASH score 32.8, Constant score 60.0, GAD-7 score 3.2, CSS 3.1. For the group B shown these mean values: DASH score 33.6, Constant score 52.9, GAD-7 score 4.3, CSS 4.5. We demonstrated a better clinical and psychological outcome at T2 in the group treated with osteosynthesis compared to the group treated with arthroplasty (Constant P = 0.049, GAD-7 P = 0.012 and CSS P = 0.005). A better clinical and psychological outcome emerged in control group at T2 comparing with surgical group (DASH score P = 0.014, Constant score P < 0.001, GAD-7 P = 0.002 and CSS P = 0.001). CONCLUSION: Both open osteosynthesis and reverse shoulder arthroplasty are valid treatments for proximal humeral fractures. According to the best osteosynthesis results the authors suggested to perform a psychological analysis for each patient in order to choose the appropriate treatment.

Thermal versus cooled radiofrequency in patients with sacroiliac joint pain: a systematic review of the literature and pooled analysis of clinical outcomes.

INTRODUCTION: Chronic low back pain (LBP) can be caused by sacroiliac joint (SIJ) disease. Many conditions could cause SIJ dysfunction. The lateral branches of the L4-S3 dorsal rami are responsible for the primary innervation of the posterior SI joint. Radiofrequency (RF) denervation represent an emerging promising treatment for refractory sacroiliac joint pain. There are different types of RF denervation such as thermal or cooled. Use of irrigation cooled electrodes allows targeted tissues to reach the neuroablative temperatures slowly, preventing collateral damage of adjacent tissue. EVIDENCE ACQUISITION: We conducted electronic database (PubMed, Medline, Cochrane and Google Scholar) research (time frame: January 1st, 2010 to May 31st, 2021) for clinical studies that had tested conventional radiofrequency (RFT) and cooled radiofrequency (RFC) to treat sacroiliac joint pain. These studies were evaluated according to Level of Evidence. Quantitative assessment of qualifying studies was done using the random effects model. We calculated the pooled size effect using standardized mean difference (SMD) as the main effect measure. EVIDENCE SYNTHESIS: We identified nine studies, with a total of 276 patients affected by sacroiliac joint pain and treated with radiofrequency. The analysis revealed a small and non-significant difference in pain reduction and an improvement in quality of life in RFT subgroup (Pain measured in Visual Analogic Scale: RFT subgroups SMD=-3.643 (95% CI -4.478, -2.807), RFC subgroup SMD=-3.285 (95% CI -4.428, -2.141), P=0.587; Quality of Life measured in Oswestry Disability Index: RFT subgroup SMD=-35.969 (95% CI -53.993%, -17.945%), RFC subgroup SMD=-20.589% (95% CI -33.424%. -7.754%), P=0.123). Publication bias was found in quality-of-life assessment due to the low number and high heterogeneity of studies. Two techniques showed no major complications. CONCLUSIONS: Current evidence indicates no statistical difference between two techniques examined. The literature is currently lacking, and well-constructed randomized clinical trials are necessary to evaluate this deficient aspect.

The epidemiology of proximal femur fractures during COVID-19 emergency in Italy: a multicentric study.

BACKGROUND AND AIM: After the first Italian case of Covid-19, the Government imposed the complete closure of all areas involved by the spread of the virus to contain transmissions. There was a massive reorganization of Hospitals, a stop of all elective activities and a convertion of many hospitals in "Covid Centers''. AITOG (Associazione Italiana Traumatologia e Ortopedia Geriatrica) conducted a retrospective study on all proximal femur fractures surgeries that occurred in this period, to find out whether the pandemic and the correlated lockdown somehow changed the incidence of these events.  Methods: 10 Italian orthopedic centers were involved in the study. Considering the geographic location, three groups were created (North, Centre and South). The considered period is the Italian "Phase 1" (February 23rd - May 3rd 2020). RESULTS: the cohort is composed of 412 patients, 116 male and 296 female (mean age 81.1 ± 9.1 years). The same period of 2019 has been used as control group, with 558 patients, 156 male and 402 female (mean age 84.2 ± 8.0 years). In 2020 we counted 323 (78.4%) fractures occurred at home, 61 (14.8%) in retirement houses and 28 (6.8%) in different locations. We mainly treated fractures with intramedullary nails (n.237 57.5%). Among all patients we had 46 (11.1%) Covid-19 positive. The mortality rate within 30 days was of 51 patients (12.4%); 23 of these died because of complications related to Covid-19 while 31 of  these were in treatment with anticoagulant/antiaggregant. CONCLUSIONS: AITOG analysis demonstrates a decrease in surgical interventions for proximal femur fractures from 2019 to 2020, a reduction in patients mean age and an increase in trauma occurred in domestic environment. We also registered a consistent difference between the North, Center and South of the Country.

The Mitochondrial Trigger in an Animal Model of Nonalcoholic Fatty Liver Disease.

Nonalcoholic fatty liver disease (NAFLD) is the leading liver chronic disease featuring hepatic steatosis. Mitochondrial ß-oxidation participates in the derangement of lipid metabolism at the basis of NAFLD, and mitochondrial oxidative stress contributes to the onset of the disease. We evaluated the presence and effects of mitochondrial oxidative stress in the liver from rats fed a high-fat plus fructose (HF-F) diet inducing NAFLD. Supplementation with dehydroepiandrosterone (DHEA), a multitarget antioxidant, was tested for efficacy in delaying NAFLD. A marked mitochondrial oxidative stress was originated by all diets, as demonstrated by the decrease in Superoxide Dismutase 2 (SOD2) and Peroxiredoxin III (PrxIII) amounts. All diets induced a decrease in mitochondrial DNA content and an increase in its oxidative damage. The diets negatively affected mitochondrial biogenesis as shown by decreased peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α), mitochondrial transcription factor A (TFAM), and the COX-IV subunit from the cytochrome c oxidase complex. The reduced amounts of Beclin-1 and lipidated LC3 II form of the microtubule-associated protein 1 light chain 3 (LC3) unveiled the diet-related autophagy's decrease. The DHEA supplementation did not prevent the diet-induced changes. These results demonstrate the relevance of mitochondrial oxidative stress and the sequential dysfunction of the organelles in an obesogenic diet animal model of NAFLD.

Quality of Life and Clinical Evaluation of Calcaneoplasty with a Balloon System for Calcaneal Fracture at 5 Years of Follow-Up.

Calcaneal fractures are a challenging clinical problem. Management of this type of injury remains controversial, especially in the context of intra-articular fractures. Surgical treatment with open reduction and internal synthesis (ORIF) is considered the standard treatment for CF, but it is associated with many complications. Several minimally invasive techniques such as balloon-assisted reduction, pin fixation, and tricalcium phosphate augmentation have been proposed to avoid the frequent and recurrent postoperative problems related to these fractures. We retrospectively examined 20 patients (mean age was 54.5), all undergoing minimally invasive calcaneoplasty surgery at our Department of Orthopaedics and Traumatology between 2012 and 2016. X-ray and CT scan were performed preoperatively and at 5 years of follow-up (57.9 ± 6 months). The American Orthopaedic Foot and Ankle Society (AOFAS) score was used for clinical examination, and the Short-Form (36) Health Survey (SF-36) score and Visual Analogue Scale (VAS) were used to assess the Health-Related Quality of Life (HRQoL). All 20 patients were available at the final follow-up. The mean AOFAS score was 82.25/100. The VAS results attest an overall average of 2.7/10 (0-9). The average of the parameters "Physical Health" and "Mental Health" was, respectively, 81.25 and 83.55. In terms of postoperative complications, we observed no cases of superficial or deep infections. Clinical response after balloon-assisted reduction, pin fixation, and tricalcium phosphate augmentation has shown a comparable or better outcome according to the AOFAS and VAS score. Quality-of-life scores, obtained according to the SF-36 questionnaire, are considered high. From both a clinical and quality-of-life point of view, our study highlights that there is not gender distinction. Further comparative studies with a higher number of patients are needed which assess the quality of life in the various techniques used to treat calcaneal fractures.

Mitochondrial Caseinolytic Protease P: A Possible Novel Prognostic Marker and Therapeutic Target in Cancer.

Caseinolytic protease P (ClpP) is a mitochondrial serine protease. In mammalian cells, the heterodimerization of ClpP and its AAA+ ClpX chaperone results in a complex called ClpXP, which has a relevant role in protein homeostasis and in maintaining mitochondrial functionality through the degradation of mitochondrial misfolded or damaged proteins. Recent studies demonstrate that ClpP is upregulated in primary and metastatic human tumors, supports tumor cell proliferation, and its overexpression desensitizes cells to cisplatin. Interestingly, small modulators of ClpP activity, both activators and inhibitors, are able to impair oxidative phosphorylation in cancer cells and to induce apoptosis. This review provides an overview of the role of ClpP in regulating mitochondrial functionality, in supporting tumor cell proliferation and cisplatin resistance; finally, we discuss whether this protease could represent a new prognostic marker and therapeutic target for the treatment of cancer.

Volar locking plate versus external fixation in distal radius fractures: A meta-analysis.

The purpose of this meta-analysis is to evaluate the efficacy of plate or external fixator treatments in distal radius fractures, based not only on clinical and radiographic parameters but on Health Related Quality of Life (HRQOL) parameters. The Preferred Reporting Items for Systematic Reviews and Metanalyses (PRISMA) guidelines were followed when conducting this systematic review. The Revised Assessment of Multiple Systematic Reviews (RAMSTAR) checklist was additionally consulted in order to ensure a high-quality methodological process, encompassing such elements as an 'a priori' design, independent reviews and comprehensive search. The literature search was carried out on PubMed, MEDLINE and Scopus. The search terms used were "Radius fracture AND osteosynthesis", "Wrist fracture AND external fixator" and "Wrist fracture AND plate". Two reviewers independently screened titles, abstracts and full texts. To determine inter-reviewer agreement, a k score was calculated after each screening state. Of the 5753 studies collected through the initial databases search, two studies were included in the final meta-analysis (125 treated with external fixator vs 132 with volar plate). There was a substantial inter-reviewer agreement as to the title (0.73; 95% confidence interval, 0.67-0.79) abstract (0.65; 95% CI, 0.46-0.83) and fulltext screening stages (0.89; 95%CI, 0.67-1). The meta-analysis reported a mean difference equal to 0.00 (95%CI= -0.05 - 0.05), in accordance with I2= 0% and p test for the heterogeneity value=0.089. This meta analysis confirms and quantifies that the two techniques are superimposable as regards the quality of life reported by patients at least one year of follow-up.

The Ketogenic Diet Reduces the Harmful Effects of Stress on Gut Mitochondrial Biogenesis in a Rat Model of Irritable Bowel Syndrome.

Functional alterations in irritable bowel syndrome have been associated with defects in bioenergetics and the mitochondrial network. Effects of high fat, adequate-protein, low carbohydrate ketogenic diet (KD) involve oxidative stress, inflammation, mitochondrial function, and biogenesis. The aim was to evaluate the KD efficacy in reducing the effects of stress on gut mitochondria. Newborn Wistar rats were exposed to maternal deprivation to induce IBS in adulthood. Intestinal inflammation (COX-2 and TRL-4); cellular redox status (SOD 1, SOD 2, PrxIII, mtDNA oxidatively modified purines); mitochondrial biogenesis (PPAR-γ, PGC-1α, COX-4, mtDNA content); and autophagy (Beclin-1, LC3 II) were evaluated in the colon of exposed rats fed with KD (IBD-KD) or standard diet (IBS-Std), and in unexposed controls (Ctrl). IBS-Std rats showed dysfunctional mitochondrial biogenesis (PPAR-γ, PGC-1α, COX-4, and mtDNA contents lower than in Ctrl) associated with inflammation and increased oxidative stress (higher levels of COX-2 and TLR-4, SOD 1, SOD 2, PrxIII, and oxidatively modified purines than in Ctrl). Loss of autophagy efficacy appeared from reduced levels of Beclin-1 and LC3 II. Feeding of animals with KD elicited compensatory mechanisms able to reduce inflammation, oxidative stress, restore mitochondrial function, and baseline autophagy, possibly via the upregulation of the PPAR-γ/PGC-1α axis.

The Age-Sensitive Efficacy of Calorie Restriction on Mitochondrial Biogenesis and mtDNA Damage in Rat Liver.

Calorie restriction (CR) is the most efficacious treatment to delay the onset of age-related changes such as mitochondrial dysfunction. However, the sensitivity of mitochondrial markers to CR and the age-related boundaries of CR efficacy are not fully elucidated. We used liver samples from ad libitum-fed (AL) rats divided in: 18-month-old (AL-18), 28-month-old (AL-28), and 32-month-old (AL-32) groups, and from CR-treated (CR) 28-month-old (CR-28) and 32-month-old (CR-32) counterparts to assay the effect of CR on several mitochondrial markers. The age-related decreases in citrate synthase activity, in TFAM, MFN2, and DRP1 protein amounts and in the mtDNA content in the AL-28 group were prevented in CR-28 counterparts. Accordingly, CR reduced oxidative mtDNA damage assessed through the incidence of oxidized purines at specific mtDNA regions in CR-28 animals. These findings support the anti-aging effect of CR up to 28 months. Conversely, the protein amounts of LonP1, Cyt c, OGG1, and APE1 and the 4.8 Kb mtDNA deletion content were not affected in CR-28 rats. The absence of significant differences between the AL-32 values and the CR-32 counterparts suggests an age-related boundary of CR efficacy at this age. However, this only partially curtails the CR benefits in counteracting the generalized aging decline and the related mitochondrial involvement.

Irisin Correlates Positively With BMD in a Cohort of Older Adult Patients and Downregulates the Senescent Marker p21 in Osteoblasts.

Irisin is a myokine produced by skeletal muscle during exercise in both mice and humans. We previously showed that irisin treatment ameliorates immobility-induced osteoporosis and muscular atrophy in mice. Data in humans showed a positive association between irisin and bone mineral density (BMD) in athletes and a population of healthy children. However, the role of this myokine regarding the state of muscle and bone in the same population remained to be determined. For this purpose, 62 patients (age 68.71 ± 12.31 years) undergoing total hip or knee replacement were recruited. Our results showed that irisin serum levels negatively correlated with age (R = -0.515; p = .000018) and positively correlated with femoral BMD (R = 0.619; p = .001) and vertebral BMD (R = 0.201; p = .0001). Irisin was also positively associated with Fndc5 mRNA in muscle biopsies (R = 0.248; p = .016), as well as with Osteocalcin (Ocn) mRNA in bone biopsies (R = 0.708; p = .006). In skeletal muscle, FNDC5 positive fibers positively correlate with BMD of total femur (R = 0.765; p = .0014) and BMD of femoral neck (R = 0.575; p = .031), Interestingly, by analyzing patients divided by their T-score, we found lower irisin levels (p = .0011) in patients with osteopenia/osteoporosis (OP) compared to healthy controls matched for age and sex. By analyzing the senescence marker p21, we found a significant increase of its mRNA expression in the bone biopsies of OP patients compared to control ones. Therefore, we investigated in vitro whether rec-irisin had a direct effect on this senescence marker, showing that p21 mRNA expression was significantly downregulated in osteoblasts by the treatment with irisin. Overall, these results indicate that higher irisin levels are associated with a lower rate of age-related osteoporosis and that irisin could be effective in delaying the osteoblast aging process, suggesting a potential senolytic action of this myokine. © 2020 American Society for Bone and Mineral Research (ASBMR).