cytochrome-c-t and Muscular-Atrophy

Apoptosis results in DNA fragmentation and, subsequently, destruction of cells containing a single nucleus. Our hypothesis is that multinucleated cells such as muscle fibers can experience apoptotic-induced loss of single nuclei (nuclear apoptosis) without destruction of the entire fiber. The loss of nuclei likely contributes to atrophy and sarcopenia. Furthermore, increased chronic activity attenuates apoptotic signaling, which may reduce sarcopenia.

Topics: Aging; Animals; Apoptosis; Cell Nucleus; Cytochromes c; Exercise; Humans; Muscle Contraction; Muscle, Skeletal; Muscular Atrophy; Satellite Cells, Skeletal Muscle

The underlying mechanisms that hibernators deviated from muscle atrophy during prolonged hibernating inactivity remain elusive. This study tested the hypothesis that the maintenance of intracellular Ca(2+) homeostasis and inhibition of apoptosis would be responsible for preventing muscle atrophy in hibernating Daurian ground squirrels. The results showed that intracellular Ca(2+) homeostasis was maintained in soleus and extensor digitorum longus (EDL) in hibernation and post-hibernation, while cytosolic Ca(2+) was overloaded in gastrocnemius (GAS) in hibernation with a recovery in post-hibernation. The Ca(2+) overload was also observed in interbout arousals in all three type muscles. Besides, the Bax/Bcl-2 ratio was unchanged in transcriptional level among pre-hibernation, hibernation and interbout arousals, and reduced to a minimum in post-hibernation. Furthermore, the Bax/Bcl-2 ratio in protein level was reduced in hibernation but recovered in interbout arousals. Although cytochrome C was increased in GAS and EDL in post-hibernation, no apoptosis was observed by TUNEL assay. These findings suggested that the intracellular Ca(2+) homeostasis in hibernation might be regulated by the cytosolic Ca(2+) overload during interbout arousals, which were likely responsible for preventing muscle atrophy via inhibition of apoptosis. Moreover, the muscle-specificity indicated that the different mechanisms against disuse-induced atrophy might be involved in different muscles in hibernation.

Topics: Animals; Apoptosis; bcl-2-Associated X Protein; Body Weight Maintenance; Calcium; Cytochromes c; DNA Fragmentation; Female; Gene Expression; Hibernation; Homeostasis; Male; Muscle, Skeletal; Muscular Atrophy; Myosin Heavy Chains; Proto-Oncogene Proteins c-bcl-2; Sciuridae

Mitochondrial morphological and ultrastructural changes occur during apoptosis and autophagy, but whether they are relevant in vivo for tissue response to damage is unclear. Here we investigate the role of the optic atrophy 1 (OPA1)-dependent cristae remodeling pathway in vivo and provide evidence that it regulates the response of multiple tissues to apoptotic, necrotic, and atrophic stimuli. Genetic inhibition of the cristae remodeling pathway in vivo does not affect development, but protects mice from denervation-induced muscular atrophy, ischemic heart and brain damage, as well as hepatocellular apoptosis. Mechanistically, OPA1-dependent mitochondrial cristae stabilization increases mitochondrial respiratory efficiency and blunts mitochondrial dysfunction, cytochrome c release, and reactive oxygen species production. Our results indicate that the OPA1-dependent cristae remodeling pathway is a fundamental, targetable determinant of tissue damage in vivo.

Topics: Animals; Cytochromes c; GTP Phosphohydrolases; Mice; Mice, Transgenic; Mitochondria; Muscular Atrophy; Oxygen Consumption; Reactive Oxygen Species

This study aimed to clarify the influence of a low-temperature environment on muscle atrophy and apoptosis.. Wistar rats were divided into four groups: two groups of hindlimb-unloading rats maintained in a normal (25°C, HU) or low-temperature (10°C, HU+LT) environment for 3 weeks and two corresponding control groups (CON; normal temperature, CON+LT; low-temperature).. The soleus muscle wet weight and muscle-to-body mass ratio were lower in the experimental groups than in the control groups. The cross-sectional areas of myofibers in the HU+LT and HU groups were significantly decreased than those in the CON and CON+LT groups. Ubiquitin ladder levels from soleus muscle lysates were significantly increased in the HU+LT group. Caspase-3-activated myofibers were observed only in the HU+LT group. Decreased cytochrome c levels were present in these caspase-3-activated myofibers. Meanwhile, cytochrome c levels were increased significantly in CON+LT rats but unchanged in HU+LT rats.. Our results suggest that apoptosis caused by hindlimb unloading at low temperatures is associated with a lack of cytochrome c in myofibers. This indicates that long-term hindlimb unloading at low temperatures did not suppress muscle atrophy. We conclude that low-temperature stimulation should not be used as a long-term treatment for preventing disuse atrophy.

Topics: Animals; Apoptosis; Cold Temperature; Cytochromes c; Fluorescent Antibody Technique; Hindlimb Suspension; Male; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy; Rats; Rats, Wistar

Muscle atrophy is a determinant of exercise capacity in heart failure (CHF). Myocyte apoptosis, triggered by tumor necrosis factor-alpha (TNF-alpha) or its second messenger sphingosine (SPH), is one of the causes of atrophy. Growth hormone (GH) improves hemodynamic and cardiac trophism in several experimental models of CHF, but its effect on skeletal muscle in CHF is not yet clear. We tested the hypothesis that GH can prevent skeletal muscle apoptosis in rats with CHF. CHF was induced by injecting monocrotaline. After 2 wk, 2 groups of rats were treated with GH (0.2 mg.kg(-1).day(-1) and 1.0 mg.kg(-1).day(-1)) subcutaneously. A third group of controls had saline. After 2 additional weeks, rats were killed. Tibialis anterior cross-sectional area, myosin heavy chain (MHC) composition, and a study on myocyte apoptosis and serum levels of TNF-alpha and SPH were carried out. The number of apoptotic nuclei, muscle atrophy, and serum levels of TNF-alpha and SPH were decreased with GH at high but not at low doses compared with CHF rats. Bcl-2 was increased, whereas activated caspases and bax were decreased. The MHC pattern in GH-treated animals was similar to that of controls. Monocrotaline slowed down both contraction and relaxation but did not affect specific tetanic force, whereas absolute force was decreased. GH treatment restored contraction and relaxation to control values and brought muscle mass and absolute twitch and tetanic tension to normal levels. These findings may provide an insight into the therapeutic strategy of GH given to patients with CHF to improve exercise capacity.

Topics: Angiotensin II; Animals; Apoptosis; Body Weight; Cardiac Output, Low; Caspases; Cytochromes c; Human Growth Hormone; In Situ Nick-End Labeling; Insulin-Like Growth Factor I; Isometric Contraction; Male; Monocrotaline; Muscle, Skeletal; Muscular Atrophy; Myosin Heavy Chains; Physical Endurance; Rats; Rats, Sprague-Dawley; Sphingosine; Tumor Necrosis Factor-alpha

Muscle proteolysis from catabolic conditions, including chronic kidney disease, requires coordinated activation of both the apoptotic and ATP-ubiquitin-proteasome systems (Ub-P'some), including upregulation of components of the Ub-P'some system. Activation of the apoptotic system is required because caspase-3 initially cleaves myofibrils, yielding substrates for the Ub-P'some system plus a characteristic 14-kD actin fragment. The authors studied insulin deficiency, a model of accelerated muscle atrophy, to understand how regulation of the apoptotic and the Ub-P'some systems could be coordinated. As expected, phosphatidylinositol 3 kinase activity (PI3K) was suppressed in muscle; in addition to decreased insulin, the mechanism includes IRS-1 phosphorylation at serine-307. Caspase-3 activity was also increased, and the authors linked it to a low PI3K-induced activation of the apoptotic system that includes a conformational change in Bax and release of cytochrome C. Coordinated atrogin-1/MAFbx expression is required as a critical factor for Ub-P'some system-dependent muscle proteolysis in diabetes and other catabolic states. The mechanism that regulates atrogin-1/MAFbx expression is unknown. Atrogin-1/MAFbx expression increased when the authors suppressed PI3K activity in muscle cells. The forkhead transcriptional factor, a downstream substrate of PI3K, stimulated atrogin-1/MAFbx promoter transcriptional activity markedly. The authors found in diabetic muscle that mRNA of the forkhead transcriptional factor, its nuclear translocation, and binding to the atrogin-1/MAFbx promoter were increased. When PI3K activity is low, both apoptotic and Ub-P'some pathways are activated coordinately to cause muscle proteolysis. This mechanism could increase muscle atrophy in conditions with impaired insulin responsiveness.

Topics: Actins; Adenosine Triphosphate; Animals; Apoptosis; Caspase 3; Caspases; Cell Line; Cysteine Endopeptidases; Cytochromes c; Enzyme Activation; Immunohistochemistry; Insulin; Male; Multienzyme Complexes; Muscles; Muscular Atrophy; Phosphatidylinositol 3-Kinases; Phosphorylation; Plasmids; Precipitin Tests; Proteasome Endopeptidase Complex; Protein Conformation; Rats; Rats, Sprague-Dawley; RNA, Messenger; Serine; Signal Transduction; Transcription, Genetic; Ubiquitin; Up-Regulation

Topics: Bulbar Palsy, Progressive; Child; Cytochromes; Cytochromes c; Electromyography; Facial Paralysis; Hemiplegia; Humans; Muscular Atrophy; Paralysis; Plastics; Surgery, Plastic