Oxidative stress and muscle homeostasis

Purpose of review The term oxidative stress is often used to indicate a condition in which the accumulation of reactive oxygen species is considered just damaging. We will discuss both the physiological and pathological role of oxidative stress on skeletal muscle homeostasis and function, and how oxidative stress can activates opposite signaling molecule to regulate gene and protein expression to guarantee muscle adaptation and to trigger a pathological condition. Recent findings Emerging evidences have assigned a critical role to oxidative stress in muscle homeostasis and in the physiopathology of skeletal muscle, suggesting that reactive oxygen species are not merely damaging agent inflicting random destruction to the cell structure and function, but useful signaling molecules to regulate growth, proliferation, differentiation, and adaptation, at least within physiological concentration. Summary The role of oxidative stress on muscle homeostasis is quite complex. It is clear that transiently increased levels of oxidative stress might reflect a potentially health promoting process, whereas an uncontrolled accumulation of oxidative stress might have pathological implication. Additional work is, therefore, necessary to understand and define precisely whether the manipulation of the redox balance represents a useful approach in the design of therapeutic strategies for muscle diseases.PURPOSE OF REVIEW: The term oxidative stress is often used to indicate a condition in which the accumulation of reactive oxygen species is considered just damaging. We will discuss both the physiological and pathological role of oxidative stress on skeletal muscle homeostasis and function, and how oxidative stress can activates opposite signaling molecule to regulate gene and protein expression to guarantee muscle adaptation and to trigger a pathological condition. RECENT FINDINGS: Emerging evidences have assigned a critical role to oxidative stress in muscle homeostasis and in the physiopathology of skeletal muscle, suggesting that reactive oxygen species are not merely damaging agent inflicting random destruction to the cell structure and function, but useful signaling molecules to regulate growth, proliferation, differentiation, and adaptation, at least within physiological concentration. SUMMARY: The role of oxidative stress on muscle homeostasis is quite complex. It is clear that transiently increased levels of oxidative stress might reflect a potentially health promoting process, whereas an uncontrolled accumulation of oxidative stress might have pathological implication. Additional work is, therefore, necessary to understand and define precisely whether the manipulation of the redox balance represents a useful approach in the design of therapeutic strategies for muscle diseases

HDAC4 preserves skeletal muscle structure following long-term denervation by mediating distinct cellular responses

BACKGROUND: Denervation triggers numerous molecular responses in skeletal muscle, including the activation of catabolic pathways and oxidative stress, leading to progressive muscle atrophy. Histone deacetylase 4 (HDAC4) mediates skeletal muscle response to denervation, suggesting the use of HDAC inhibitors as a therapeutic approach to neurogenic muscle atrophy. However, the effects of HDAC4 inhibition in skeletal muscle in response to long-term denervation have not been described yet. METHODS: To further study HDAC4 functions in response to denervation, we analyzed mutant mice in which HDAC4 is specifically deleted in skeletal muscle. RESULTS: After an initial phase of resistance to neurogenic muscle atrophy, skeletal muscle with a deletion of HDAC4 lost structural integrity after 4 weeks of denervation. Deletion of HDAC4 impaired the activation of the ubiquitin-proteasome system, delayed the autophagic response, and dampened the OS response in skeletal muscle. Inhibition of the ubiquitin-proteasome system or the autophagic response, if on the one hand, conferred resistance to neurogenic muscle atrophy; on the other hand, induced loss of muscle integrity and inflammation in mice lacking HDAC4 in skeletal muscle. Moreover, treatment with the antioxidant drug Trolox prevented loss of muscle integrity and inflammation in in mice lacking HDAC4 in skeletal muscle, despite the resistance to neurogenic muscle atrophy. CONCLUSIONS: These results reveal new functions of HDAC4 in mediating skeletal muscle response to denervation and lead us to propose the combined use of HDAC inhibitors and antioxidant drugs to treat neurogenic muscle atrophy

inhibition of osteoclast activity by complement regulation with df3016a a novel small molecular weight c5ar inhibitor

Abstract Recent insights have indicated an active role of the complex complement system not only in immunity, but also in bone remodeling. Evidence from knockout mice and observations from skeletal diseases have drawn attention to the C5a/C5aR axis of the complement cascade in the modulation of osteoclast functions and as potential therapeutic targets for treatment of bone pathologies. With the aim to identify novel C5aR regulators, a medicinal chemistry program was initiated, driven by structural information on a minor pocket of C5aR that has been proposed to be a key motif for C5aR intracellular activation. The impact of the peptidomimetic orthosteric C5aR antagonist (PMX-53), of two newly synthesized allosteric C5aR antagonists (DF2593A, DF3016A), and of C5aR down-regulation by specific siRNAs, were examined for regulation of osteoclastogenesis, using a well-validated in-vitro model starting from RAW264.7 precursor cells. Both pharmacological and molecular approaches reduced osteoclast maturation of RAW264.7 cells induced by receptor-activator of nuclear factor kappa-B ligand (RANKL), which limited the transcription of several differentiation markers evaluated by real-time PCR, including nuclear factor of activated T-cell 1, matrix metalloproteinase-9, cathepsin-K, and tartrate-resistant acid phosphatase. These treatments were ineffective on the subsequent step of osteoclast syncytium formation, apparently as a consequence of reduction of C5aR mRNA levels in the course of osteoclastogenesis, as monitored by real-time PCR. Among the C5aR antagonists analyzed, DF3016A inhibited osteoclast degradation activity through inhibition of C5aR signal transduction and transcription. These data confirm the preclinical relevance of this novel therapeutic candidate

Synthetic Scaffold/Dental Pulp Stem Cell (DPSC) Tissue Engineering Constructs for Bone Defect Treatment: An Animal Studies Literature Review

Background: Recently a greater interest in tissue engineering for the treatment of large bone defect has been reported. The aim of the present systematic review and meta-analysis was to investigate the effectiveness of dental pulp stem cells and synthetic block complexes for bone defect treatment in preclinical in vivo articles. Methods: The electronic database and manual search was conducted on Pubmed, Scopus, and EMBASE. The papers identified were submitted for risk-of-bias assessment and classified according to new bone formation, bone graft characteristics, dental pulp stem cells (DPSCs) culture passages and amount of experimental data. The meta-analysis assessment was conducted to assess new bone formation in test sites with DPSCs/synthetic blocks vs. synthetic block alone. Results: The database search identified a total of 348 papers. After the initial screening, 30 studies were included, according to the different animal models: 19 papers on rats, 3 articles on rabbits, 2 manuscripts on sheep and 4 papers on swine. The meta-analysis evaluation showed a significantly increase in new bone formation in favor of DPSCs/synthetic scaffold complexes, if compared to the control at 4 weeks (Mean Diff: 17.09%, 95% CI: 15.16–18.91%, p < 0.01) and at 8 weeks (Mean Diff: 14.86%, 95% CI: 1.82–27.91%, p < 0.01) in rats calvaria bone defects. Conclusion: The synthetic scaffolds in association of DPSCs used for the treatment of bone defects showed encouraging results of early new bone formation in preclinical animal studies and could represent a useful resource for regenerative bone augmentation procedure

Denervation does not induce muscle atrophy through oxidative stress

Denervation leads to the activation of the catabolic pathways, such as the ubiquitin-proteasome and autophagy, resulting in skeletal muscle atrophy and weakness. Furthermore, denervation induces oxidative stress in skeletal muscle, which is thought to contribute to the induction of skeletal muscle atrophy. Several muscle diseases are characterized by denervation, but the molecular pathways contributing to muscle atrophy have been only partially described. Our study delineates the kinetics of activation of oxidative stress response in skeletal muscle following denervation. Despite the denervation-dependent induction of oxidative stress in skeletal muscle, treatments with anti-oxidant drugs do not prevent the reduction of muscle mass. Our results indicate that, although oxidative stress may contribute to the activation of the response to denervation, it is not responsible by itself of oxidative damage or neurogenic muscle atrophy

Functional characterization of muscle fibres from patients with chronic fatigue syndrome: case-control study

Chronic fatigue syndrome (CFS) is a disabling condition characterized by unexplained chronic fatigue that impairs normal activities. Although immunological and psychological aspects are present, symptoms related to skeletal muscles, such as muscle soreness, fatigability and increased lactate accumulation, are prominent in CFS patients. In this case-control study, the phenotype of the same biopsy samples was analyzed by determining i) fibre-type proportion using myosin isoforms as fibre type molecular marker and gel electrophoresis as a tool to separate and quantify myosin isoforms, and ii) contractile properties of manually dissected, chemically made permeable and calcium-activated single muscle fibres. The results showed that fibre-type proportion was significantly altered in CSF samples, which showed a shift from the slow- to the fast-twitch phenotype. Cross sectional area, force, maximum shortening velocity and calcium sensitivity were not significantly changed in single muscle fibres from CSF samples. Thus, the contractile properties of muscle fibres were preserved but their proportion was changed, with an increase in the more fatigue-prone, energetically expensive fast fibre type. Taken together, these results support the view that muscle tissue is directly involved in the pathogenesis of CSF and it might contribute to the early onset of fatigue typical of the skeletal muscles of CFS patients

Transcription profile analysis of vastus lateralis muscle from patients with chronic fatigue syndrome.

Chronic fatigue syndrome (CFS) is a disabling condition characterized by unexplained chronic fatigue that impairs normal activities. Many body systems are affected and etiology has not yet been identified. In addition to immunological and psychological aspects, skeletal muscle symptoms are prominent in CFS patients. In an effort to establish which pathways might be involved in the onset and development of muscle symptoms, we used global transcriptome analysis to identify genes that were differentially expressed in vastus lateralis muscle of female and male CFS patients. We found that the expression of genes that play key roles in mitochondrial function and oxidative balance, including superoxide dismutase 2, were altered, as were genes involved in energy production, muscular trophism and fiber phenotype determination. Importantly, the expression of a gene encoding a component of the nicotinic cholinergic receptor binding site was reduced, suggesting impaired neuromuscular transmission. We argue that these major biological processes could be involved in and/or responsible for the muscle symptoms of CFS

Myomir dysregulation and reactive oxygen species in aged human satellite cells

AbstractSatellite cells that reside on the myofibre surface are crucial for the muscle homeostasis and regeneration. Aging goes along with a less effective regeneration of skeletal muscle tissue mainly due to the decreased myogenic capability of satellite cells. This phenomenon impedes proper maintenance and contributes to the age-associated decline in muscle mass, known as sarcopenia. The myogenic potential impairment does not depend on a reduced myogenic cell number, but mainly on their difficulty to complete a differentiation program. The unbalanced production of reactive oxygen species in elderly people could be responsible for skeletal muscle impairments. microRNAs are conserved post-transcriptional regulators implicated in numerous biological processes including adult myogenesis. Here, we measure the ROS level and analyze myomiR (miR-1, miR-133b and miR-206) expression in human myogenic precursors obtained from Vastus lateralis of elderly and young subjects to provide the molecular signature responsible for the differentiation impairment of elderly activated satellite cells

Old muscle in young body: an aphorism describing the Chronic Fatigue Syndrome

The chronic fatigue syndrome (CFS) otherwise known as myalgic encephalomyelitis (ME), is a debilitating syndrome whose identification is very complex due to lack of precise diagnostic criteria. This pathology begins with limitations in duration and intensity of exercise and rapid onset of pain during physical activity. Its etiology is unknown, and symptoms are not limited to the muscles. Epidemiology is rather difficult to delimit, even if it affects mainly young (20-40 years), female subjects. The results of muscular research show some peculiarities that can justify what has been observed in vivo. In particular, 1. presence of oxidative damage of lipid component of biological membranes and DNA not compensated by the increase of the scavenger activity; 2. Excitation-Contraction (E-C) alteration with modification of Ca2+ transport; 3. passage from slow to fast fiber phenotype; 4. inability to increase glucose uptake; 5. presence of mitochondrial dysfunction; and 6. genes expressed differentially (particularly those involved in energy production). The skeletal muscles of CFS / ME patients show a significant alteration of the oxidative balance due to mitochondrial alteration and of the fiber phenotype composition as shown in sarcopenic muscles of the elderly. Vice versa, the muscle catabolism does not appear to be involved in the onset of this syndrome. The data support the hypothesis that patients with CFS are subjected to some of the problems typical for muscle aging, which is probably related to disorders of muscle protein synthesis and biogenesis of mitochondria. Patients with CFS can benefit from an appropriate training program because no evidence suggests that physical exercise worsens symptoms. Type, intensity and duration of any physical activity that activates muscle contraction (including Electrical Stimulation) require further investigation even if it is known that non-exhaustive physical activity decreases painful symptomatology

Electromyographic signature of isometric squat in the highest refuge in Europe

Reports of electromyography during hypoxic exercise are contrasting, due to protocol and muscle diversity. This work aimed to investigate alterations in muscle activation and myoelectrical fatigue during exercise at high-altitude in those muscles primarily involved in trekking. Twelve young adults balanced by gender and age were tested at low (1,667 m) and high (4,554 m, "Capanna Margherita", Italy) altitude, during an isometric squat lasting 60 seconds. High-density surface electromyography was performed from the quadriceps of right limb. The root mean square (RMS), median frequency with its slope, and muscle fiber conduction velocity (MFCV) were computed. Neither males nor females showed changes in median frequency (Med: 36.13 vs 35.63 Hz) and its slope (Med: -9 vs -12 degree) in response to high-altitude trekking, despite a great inter-individual heterogeneity, nor differences were found for MFCV. RMS was not significantly equivalent, with greater values at low altitude (0.385 ± 0.104 mV) than high altitude (0.346 ± 0.090 mV). Unexpected results can be due either to a postural compensation of the whole body compensating for a relatively greater effort or to the inability to support muscle activation after repeated physical efforts.  Interesting results may emerge by measuring simultaneously electromyography, muscle oxygenation and kinematics comparing trekking at normoxia vs hypoxia