The effects of exercise and mitochondrial transplantation alone or in combination against Doxorubicin-induced skeletal muscle atrophy.

Doxorubicin (DOX) is a chemotherapy drug used to treat various types of cancer, but it is associated with significant side effects such as skeletal muscle atrophy. Exercise has been found to prevent skeletal muscle atrophy through the modulation of mitochondrial pathways. Mitochondrial transplantation (MT) may mitigate toxicity, neurological disorders, kidney and liver injury, and skeletal muscle atrophy. The objective of this study was to evaluate the effects of MT, exercise, and MT with exercise on DOX-induced skeletal muscle atrophy. Male Sprague Dawley rats were randomly assigned to the following groups: control, DOX, MT with DOX, exercise with DOX, and exercise with MT and DOX. A 10-day treadmill running exercise and MT (6.5 µg/100 µL) to tibialis anterior (TA) muscle were administered prior to a single injection of DOX (20 mg/kg). Our data showed that exercise and MT with exercise led to an increase in cross-sectional area of the TA muscle. Exercise, MT and MT with exercise reduced inflammation and maintained mitochondrial enzyme activity. Additionally, exercise and MT have been shown to regulate mitochondrial fusion/fission. Our findings revealed that exercise and MT with exercise prevented oxidative damage. Furthermore, MT and MT with exercise decreased apoptosis and MT with exercise triggered mitochondrial biogenesis. These findings demonstrate the importance of exercise in the prevention of skeletal muscle atrophy and emphasize the significant benefits of MT with exercise. To the best of our knowledge, this is the first study to demonstrate the therapeutic effects of MT with exercise in DOX-induced skeletal muscle atrophy.

Mitochondrial dysfunction and skeletal muscle atrophy: Causes, mechanisms, and treatment strategies.

Skeletal muscle, which accounts for approximately 40% of total body weight, is one of the most dynamic and plastic tissues in the human body and plays a vital role in movement, posture and force production. More than just a component of the locomotor system, skeletal muscle functions as an endocrine organ capable of producing and secreting hundreds of bioactive molecules. Therefore, maintaining healthy skeletal muscles is crucial for supporting overall body health. Various pathological conditions, such as prolonged immobilization, cachexia, aging, drug-induced toxicity, and cardiovascular diseases (CVDs), can disrupt the balance between muscle protein synthesis and degradation, leading to skeletal muscle atrophy. Mitochondrial dysfunction is a major contributing mechanism to skeletal muscle atrophy, as it plays crucial roles in various biological processes, including energy production, metabolic flexibility, maintenance of redox homeostasis, and regulation of apoptosis. In this review, we critically examine recent knowledge regarding the causes of muscle atrophy (disuse, cachexia, aging, etc.) and its contribution to CVDs. Additionally, we highlight the mitochondrial signaling pathways involvement to skeletal muscle atrophy, such as the ubiquitin-proteasome system, autophagy and mitophagy, mitochondrial fission-fusion, and mitochondrial biogenesis. Furthermore, we discuss current strategies, including exercise, mitochondria-targeted antioxidants, in vivo transfection of PGC-1α, and the potential use of mitochondrial transplantation as a possible therapeutic approach.

Effect of teeth clenching on handgrip force in adult men: role of periodontal mechanoreceptors.

PURPOSE: Voluntary teeth clenching is shown to increase the strength of muscle reflexes contributing to the improvement of postural stability. However, the interaction between the handgrip strength and teeth clenching is not yet understood. In this study, we aimed to evaluate the change in handgrip force in response to voluntary teeth clenching, and its relation to the peripheral receptors that play a central role in the control of mastication. METHODS: Thirty-six healthy men were divided into two groups: aged 50-59 years, no dental prosthesis, and 53-62 years with total dental prosthesis. Each individual was given handgrip and teeth clenching instructions for five experiments: only handgrip, teeth clenching followed by handgrip without teeth clenching, teeth clenching followed by handgrip with teeth clenching, and the repetition of the last two instructions while wearing mouth guards. RESULTS: Our findings showed that maximum handgrip force decreased and the resistance to fatigue increased in complete edentulous individuals using appropriate prostheses. Also, the significantly lower maximum handgrip force and higher resistance to fatigue values of the participants with dental prosthesis using a mouth guard while teeth clenching, revealed the central roles of periodontal mechanoreceptors. CONCLUSION: Decreases in masticatory sensory information processes influence handgrip force values which is the most important indicator of motor function. The lack of periodontal mechanoreceptors associated with dental prosthesis usage may lead to a loss in muscle strength.

Mitochondrial transplantation as a possible therapeutic option for sarcopenia.

With advancing age, the skeletal muscle phenotype is characterized by a progressive loss of mass, strength, and quality. This phenomenon, known as sarcopenia, has a negative impact on quality of life and increases the risk of morbidity and mortality in older adults. Accumulating evidence suggests that damaged and dysfunctional mitochondria play a critical role in the pathogenesis of sarcopenia. Lifestyle modifications, such as physical activity, exercise, and nutrition, as well as medical interventions with therapeutic agents, are effective in the management of sarcopenia and offer solutions to maintain and improve skeletal muscle health. Although a great deal of effort has been devoted to the identification of the best treatment option, these strategies are not sufficient to overcome sarcopenia. Recently, it has been reported that mitochondrial transplantation may be a possible therapeutic approach for the treatment of mitochondria-related pathological conditions such as ischemia, liver toxicity, kidney injury, cancer, and non-alcoholic fatty liver disease. Given the role of mitochondria in the function and metabolism of skeletal muscle, mitochondrial transplantation may be a possible option for the treatment of sarcopenia. In this review, we summarize the definition and characteristics of sarcopenia and molecular mechanisms associated with mitochondria that are known to contribute to sarcopenia. We also discuss mitochondrial transplantation as a possible option. Despite the progress made in the field of mitochondrial transplantation, further studies are needed to elucidate the role of mitochondrial transplantation in sarcopenia. KEY MESSAGES: Sarcopenia is the progressive loss of skeletal muscle mass, strength, and quality. Although the specific mechanisms that lead to sarcopenia are not fully understood, mitochondria have been identified as a key factor in the development of sarcopenia. Damaged and dysfunctional mitochondria initiate various cellular mediators and signaling pathways, which largely contribute to the age-related loss of skeletal muscle mass and strength. Mitochondrial transplantation has been reported to be a possible option for the treatment/prevention of several diseases. Mitochondrial transplantation may be a possible therapeutic option for improving skeletal muscle health and treating sarcopenia. Mitochondrial transplantation as a possible treatment option for sarcopenia.

Pyroptosis: a new therapeutic strategy in cancer.

Programmed cell death pathways play important roles in a wide variety of physiological processes. Although it has similarities with apoptosis pyroptosis is a different type of programmed cell death. Pyroptosis can be triggered by different molecules originating from the cells or their environment. Once a pyroptotic pathway is started, it is followed by different molecular steps, and, it ends with the disruption of cell membrane integrity and the onset of inflammatory processes. In addition to the role of pyroptosis in the host's innate immunity against pathogens, uncontrolled pyroptosis can lead to increased inflammation and lead various diseases. The contradictory role of pyroptosis-related molecular changes in the pathogenesis of cancer has attracted attention lately. Excessive or decreased expression of molecules involved in pyroptotic pathways is associated with various cancers. There are ongoing studies on the use of different treatment methods for cancer in combination with new therapies targeting pyroptosis. The potential beneficial effects or side-effect profiles of these protocols targeting pyroptosis still need to be investigated. This will provide us with more efficient and safer options to treat cancer. This review aims to overview the main pathways and mechanisms of pyroptosis and to discuss its role in cancer.

Biological nerve conduit model with de-epithelialized human amniotic membrane and adipose-derived mesenchymal stem cell sheet for repair of peripheral nerve defects.

In this study, a biological conduit, consisting of an adipocyte-derived mesenchymal stem cell (AdMSCs) sheet and amniotic membrane (AM), was designed for the reconstruction of peripheral nerve defects. To evaluate the effect of the produced conduit on neural regeneration, a 10-mm sciatic nerve defect was created in rats, and experiments were carried out on six groups, i.e., sham control group (SC), negative control group (NC), nerve autograft group (NG), the biological conduit (AdMSCs + AM) group, the commercial PGA tube conduit (PGA) group, and the conduit only consisting of AM (AM) group. The effects of different nerve repair methods on the peripheral nerve and gastrocnemius muscle were evaluated by functional, histological, and immunohistochemical tests. When the number of myelinated axons was compared between the groups of AdMSCs + AM and PGA, it was higher in the AdMSCs + AM group (p < 0.05). The percentage of gastrocnemius collagen bundle area of AdMSCs + AM group was found to be statistically lower than the PGA group (p < 0.05). The muscle fiber diameter of AdMSCs + AM group was lower than that of the NG group, but significantly higher than that of the PGA group and the AM group (p < 0.001). Muscle weight index was significantly higher in the AdMSCs + AM group compared to the PGA group (p < 0.05). It was observed that nerve regeneration was faster in the AdMSCs + AM group, and there was an earlier improvement in pin-prick score and sciatic functional index compared to the PGA group and the AM group. In conclusion, the biological conduit prepared from the AdMSCs sheet and AM is regarded as a new biological conduit that can be used as an alternative treatment method to nerve autograft in clinical applications.

Melatonin is effective in attenuating cisplatin-induced neurotoxicity.

Cisplatin (Cis) is a chemotherapeutic agent that has many side effects. Neurotoxicity is one of the most important of these side effects. Oxidative stress and neuroinflammation are the best-known mechanisms in the pathogenesis of neurotoxicity development. In this study, we aimed to determine whether melatonin (Mel), with antioxidant and anti-inflammatory effects, is effective in preventing Cis-induced neurotoxicity. Forty-eight male Sprague-Dawley rats were divided into six groups (n = 8) as follows: control (0.9% NaCl), vehicle (5% ethanol), Cis (6 mg/kg), Cis (6 mg/kg) + vehicle (5% ethanol), Mel (20 mg/kg), and Cis (6 mg/kg) + Mel (20 mg/kg) groups. Cis was administered as a single dose on the 3rd day of the experiment while Mel was given for 5 days. All administrations were performed via intraperitoneal injection. After injections, T-maze, rotarod, and hot plate tests were performed to evaluate cognitive, motor, and sensory functions, respectively. Following sacrification oxidative stress markers, cholinergic function, and proinflammatory cytokines were studied from brain homogenates. Cis impaired cognitive function and motor performance in the Cis and Cis+Vehicle groups. The drug also increased oxidative stress in the brain. Mel significantly improved brain oxidant/antioxidant status and also decreased the overproduction of proinflammatory cytokines (superoxide dismutase activities in Cis+Vehicle and Cis+Mel groups: 104.55 ± 9.50 µU/mg protein vs. 150.13 ± 4.70 µU/mg protein, respectively, p < 0.05; tumor necrosis factor-α levels in Cis and Cis+Mel groups: 40 pg/ml vs. 20 pg/ml, respectively, p < 0.05). It seems that Mel can improve Cis neurotoxicity. For a more firm conclusion, further studies using Mel at different doses with larger groups should be performed.

Melatonin Improves Reduced Activities of Membrane ATPases and Preserves Ultrastructure of Gray and White Matter in the Rat Brain Ischemia/Reperfusion Model.

Ischemia/reperfusion (I/R) is among the most frequent neurological problems and early intervention to limit the damage is crucial in decreasing mortality and morbidity. Based on reports regarding beneficial effects of melatonin, we investigated its impact on Na+-K+/Mg2+ ATPase and Ca2+/Mg2+ ATPase activities and ultrastructure of gray and white matter in the rat forebrain I/R model. Adult Wistar-albino rats (n = 78), were randomized into control, ischemia (I), ischemia/reperfusion (I/R), low (I/R + melatonin 400 µg/kg), moderate (I/R + melatonin 1200 µg/kg), and high (I/R + melatonin 2400 µg/kg) dose melatonin. Two-vessel occlusion combined with hypotension (15 min) induced ischemia and reperfusion (75 min) achieved by blood reinfusion were performed. Activities of the membrane-bound enzyme, brain malondialdehyde levels, and brain matter ultrastructure were examined in frontoparietal cortices. Melatonin lowered production of malondialdehyde in a dose-dependently. The enzyme activities attenuated under I and I/R, improved with melatonin treatment. I and I/R severely disturbed gray and white matter morphology. Melatonin, in all applied doses, decreased ultrastructural damages in both gray and white matter. Favorable effects of melatonin can be attributed to its antioxidant properties suggesting that it could be a promising neuroprotective agent against I/R injury being effective both for gray and white matter due to favorable biological properties.

Metformin reduces ovarian ischemia reperfusion injury in rats by improving oxidative/nitrosative stress.

OBJECTIVE: To assess the preventive role of metformin on rat ovarian ischemia reperfusion injury. MATERIALS AND METHODS: Forty rats were divided equally into five groups; Group 1: sham, Group 2: surgical control with 3-hr torsion and detorsion, Group 3: 50 mg/kg p.o. metformin 30 min before 3-hr torsion, Group 4; metformin just after detorsion, Group 5; metformin 30 min before torsion and just after detorsion. Bilateral ovaries and blood sample were obtained seven days after detorsion for biochemical and histopathological evaluation. RESULTS: Ovarian tissue total anti-oxidant status (TAS) levels were significantly increased in group 4 when compared to group 1, 2 and 3 (all p < 0.01). In addition, there was a significant decrease in tissue oxidative stress index (OSI) level in group 4 with respect to group 2 (p < 0.01). Moreover, serum levels of OSI were significantly higher in group 2 with respect to group 1 and 5 (both p < 0.05). Similarly, there was significant increase in serum levels of peroxynitrite in group 2 as compared to serum levels in group 3 and 5 (p < 0.01 and 0.05, respectively). Furthermore, there were significant decrease in histopathological scores metformin and sham groups when compared to rats in the control group (Group 2). CONCLUSION: Metformin reduces ischemia reperfusion injury in rat torsion detorsion model by improving histopathological and biochemical findings including TAS, OSI and peroxynitrite.

Melatonin attenuates ovarian ischemia reperfusion injury in rats by decreasing oxidative stress index and peroxynitrite

Background/aim: To evaluate the protective effect of melatonin on ovarian ischemia reperfusion injury in a rat model. Materials and methods: Forty-eight rats were separated equally into 6 groups. Group 1: sham; Group 2: surgical control with 3-h bilateral ovarian torsion and detorsion; Group 3: intraperitoneal 5% ethanol (1 mL) just after detorsion (as melatonin was dissolved in ethanol); Group 4: 10 mg/kg intraperitoneal melatonin 30 min before 3-h torsion; Group 5:10 mg/kg intraperitoneal melatonin just after detorsion; Group 6:10 mg/kg intraperitoneal melatonin 30 min before torsion and just after detorsion. Both ovaries and blood samples were obtained 7 days after detorsion for histopathological and biochemical analysis. Results: In Group 1, serum levels of total oxidant status (TOS) (µmol H2O2 equivalent/g wet tissue)were significantly lower than in Group2 (P = 0.0023), while tissue TOS levels were lower than in Group 3 (P = 0.0030). Similarly, serum and tissue levels of peroxynitrite in Group 6were significantly lower than those ofGroup 2 (P = 0.0023 and P = 0.040, respectively). Moreover, serum oxidative stress index (OSI) (arbitrary unit) levels were significantly increased in Group 2 when compared to groups 1 and 6 (P = 0.0023 and P= 0.0016, respectively) and in Group 3 with respect to groups 1, 4, 5, and 6 (P = 0.0023, P = 0.0026, P = 0.0008, and P = 0.0011, respectively). Furthermore, there was a significant decrease in histopathological scores including follicular degeneration, vascular congestion, hemorrhage, and inflammation in the melatonin and sham groups in comparison with control groups. Additionally, primordial follicle count was significantly higher in Group 6 than in Group 2 (P = 0.0002). Conclusion: Melatonin attenuates ischemia reperfusion damage in a rat torsion/detorsion model by improving histopathological and biochemical findings including OSI and peroxynitrite.

Octreotide and lanreotide decrease ovarian ischemia-reperfusion injury in rats by improving oxidative and nitrosative stress.

AIM: To investigate the protective effect of octreotide and lanreotide on ovarian damage in experimental ovarian ischemia-reperfusion injury. METHODS: Fifty-six rats were separated into seven groups; group 1: sham group, group 2: surgical control group with 3-h torsion and detorsion, group 3: 0.02 mg/kg s.c. octreotide 30 min before 3-h torsion, group 4; octreotide just after detorsion for 7 days, group 5: octreotide 30 min before torsion and just after detorsion for 7 days, group 6: single time 20 mg/kg s.c. lanreotide before torsion, group 7: single time lanreotide just after detorsion. RESULTS: All histopathological scores except congestion were significantly lower in group 1 than other groups. In addition, hemorrhage (group 2 vs 4: P < 0.05), degeneration (group 2 vs 4: P < 0.05, group 2 vs 5: P < 0.01 and group 2 vs 6: P < 0.05) and total damage score (group 2 vs 4: P < 0.05, group 2 vs 5: P < 0.05, group 2 vs 6: P < 0.05 and group 2 vs 7: P < 0.05) were significantly lower than other groups. Moreover, ovarian tissue total oxidant status and oxidative stress index levels were significantly decreased in groups 5 (both P < 0.05) and 7 (both P < 0.05) when compared to group 2. Furthermore, tissue levels of peroxynitrite were significantly higher in group 2 than groups 1, 3 and 5 (all P < 0.05). CONCLUSIONS: Octreotide and lanreotide have a protective role against ischemia-reperfusion damage in rat torsion detorsion model by improving histopathological and biochemical findings including tissue levels of total oxidant status, oxidative stress index and peroxynitrite.

Protective role of erdosteine pretreatment on oleic acid-induced acute lung injury.

BACKGROUND: Erdosteine is a mucolytic agent with antioxidant and anti-inflammatory effects. We evaluated the protective effect of erdosteine pretreatment on oleic acid (OA)-induced acute lung injury. MATERIALS AND METHODS: Twenty-four male Wistar Albino rats were assigned to four treatments: control (oral saline + 50 µL intravenous [i.v.] saline), OA (oral saline + 50 µL i.v. OA), erdosteine (150 mg/kg oral erdosteine + 50 µL i.v. saline), and OA + erdosteine (150 mg/kg oral erdosteine + 50 µL i.v. OA). Four hours after OA injection, lung tissues were excised for biochemical and histopathologic evaluation. RESULTS: OA treatment increased lung weight and tissue malondialdehyde and protein carbonyl levels, but erdosteine pretreatment significantly suppressed these changes (0.57 ± 0.1 g, 3.27 ± 0.48 nmol/mg protein, and 33.57 ± 4.6 nmol/mg protein, respectively, for OA versus 0.36 ± 0.02 g, 1.84 ± 0.15 nmol/mg protein, and 22.10 ± 2.55 nmol/mg protein, respectively, for OA + erdosteine; P < 0.05 for all). Erdosteine pretreatment increased the activities of the antioxidant enzymes, catalase, and glutathione peroxidase (0.16 ± 0.03 k/g and 0.3 ± 0.01 U/mg protein, respectively, for OA versus 0.33 ± 0.05 k/g and 0.34 ± 0.01 U/mg protein, respectively, for OA + erdosteine; P < 0.05 for both). Erdosteine pretreatment also significantly decreased the median numbers of intra-alveolar macrophages and intra-alveolar and interstitial neutrophils (29.0, 17.0, and 15.0, respectively, for OA versus 12.5, 4.0, and 6.5, respectively, for OA + erdosteine; P < 0.001 for all). CONCLUSIONS: Erdosteine pretreatment increased the activities of antioxidant enzymes and decreased macrophage and neutrophil accumulation, thereby ameliorating the inflammatory effects of OA treatment. Erdosteine pretreatment prevents OA-induced oxidative stress and inflammation and protects the lung tissue against acute lung injury.

The role of periodontal mechanoreceptors in mastication.

The aim of this review is to discuss what is known about the reflex control of the human masticatory system by the periodontal mechanoreceptors and to put forward a method for standardised investigation. To deliver mechanical stimulus in a reproducible way, the following precautions are suggested: the stimulus should be brought into secure contact with the area of stimulation, and slack between the probe and the area to be stimulated should be taken up by the application of a preload. It is also important to ensure that there is minimal simultaneous activation of receptor systems other than the periodontal mechanoreceptors. It is also necessary to standardise the method for recording and analysing the response.

Influence of tooth clench on the soleus H-reflex.

The Hoffmann (H) reflex is elicited by electrical stimulation of a mixed nerve and is used to measure the excitability of the spindle-motoneuron synapse. Recent investigations have indicated a positive correlation between increases in bite force and H-reflex facilitation. However, these investigations did not examine the H-reflex in detail or the possible role of periodontal mechanoreceptors (PMRs) in this facilitation. The current investigation was performed to determine whether PMRs play a role in H-reflex facilitation during tooth clench (TC). The H-reflex was elicited in the soleus muscle of human subjects while bite level was maintained at rest (0 N), 40 N, 80 N and maximal TC. The front teeth that contributed to the (40 N and 80 N) bite force were then locally anaesthetised (LA), and the protocol was repeated. The current data suggest that the effect of TC on the H-reflex amplitude in the human limb muscles is variable from one subject to the next. Statistical analysis has shown that the H-reflex was significantly smaller during the rest condition than during the 80 N bite (p<0.05) in both non-LA and LA conditions. Since LA did not alter the response, our results do not support that the PMRs play a major role in the facilitation of distal muscle activity.

A review of the H-reflex and M-wave in the human triceps surae.

The soleus is the most commonly used muscle for H-reflex studies in humans, while limited comparable data have been produced from the gastrocnemii muscles. This article reviews the fundamental differences between the structure and function of the human soleus and gastrocnemii muscles, including recent data published about their complex innervation zones. Protocols for eliciting, recording, and assessing the H-reflex and M-wave magnitude in the human triceps surae are also discussed.

The Effect Of Enalapril Maleat In Ischemia Reperfusion Injury: Possible Role of Membrane Bound Enzymes.

The present study evaluates the protective effect of enalapril maleat on myocardial ischemia-reperfusion injury. Membrane bound enzymes; Na(+)K(+)/Mg(2+) ATPase and Ca(2+)/Mg(2+) ATPase are known to regulate the membrane integrity. We hypothesized that if we could protect the cell membrane in ischemia-reperfusion period, we might have a chance to augment contractility. Thirty-two Guinea pig hearts were studied in an isolated Krebs-Henseleit solution-perfused Langendorff cardiac model. In Group 1, control hearts (n = 8) were arrested with St. Thomas Cardioplegic Solution (STHCS) alone. In Group 2 (n = 8), animals were pretreated with oral enalapril maleat (0.2mg/kg/daily) for ten days and arrested with STHCS. In Group 3, (n = 8) the hearts were arrested with enalapril maleat- (1 µmol/L) added STHCS. In Group 4 (n = 8), the hearts were again pretreated with oral enalapril maleat for ten days and then reperfused with enalapril maleat-added Krebs-Henseleit solution. Hearts were subjected to normothermic global ischemia for 90 minutes and then were reperfused at 37 degrees C. The study groups showed better recovery of left ventricular systolic function. In terms of biochemical determinations, best results were achieved at Group 4. The Na(+)K(+) ATPase and Ca(2+) ATPase levels were measured at 466.38 +/- 5.99 to 545.23 +/- 8.79, and 884.69 +/- 9.13 to 1254.34 +/- 1.56, respectively (p < 0.05). Based on these results, it can be concluded that enalapril maleat protects the membrane integrity and thus plays a role in restoring the contractility in ischemia-reperfusion injury.