Mitochondrial biogenesis during skeletal muscle regeneration

2002 ◽  
Vol 282 (4) ◽  
pp. E802-E809 ◽  
Author(s):  
Stéphanie Duguez ◽  
Léonard Féasson ◽  
Christian Denis ◽  
Damien Freyssenet
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Transcriptional Activation ◽  
Muscle Regeneration ◽  
Citrate Synthase ◽  
Mrna Level ◽  
Skeletal Muscle Regeneration ◽  
Nuclear Antigen ◽  
Peroxisome Proliferator ◽  
Sprague Dawley

Myogenesis requires energy production for the execution of a number of regulatory and biosynthesis events. We hypothesized that mitochondrial biogenesis would be stimulated during skeletal muscle regeneration. Tibialis anterior muscles of male Sprague-Dawley rats were injected with 0.75% bupivacaine and removed at 3, 5, 7, 10, 14, 21, or 35 days after injection ( n = 5–7/group). Two main periods emerged from the histochemical analyses of muscle sections and the expression of proliferating cell nuclear antigen, desmin, and creatine phosphokinase: 1) activation/proliferation of satellite cells ( days 3–14) and 2) differentiation into muscle fibers ( days 5–35). The onset of muscle differentiation was accompanied by a marked stimulation of mitochondrial biogenesis, as indicated by a nearly fivefold increase in citrate synthase activity and state 3 rate of respiration between days 5 and 10. Peroxisome proliferator-activated receptor-γ coactivator-1 (PGC-1) mRNA level and mitochondrial transcription factor A (mtTFA) protein level peaked on day 10 concurrently with the state 3 rate of respiration. Therefore, transcriptional activation by PGC-1 and mtTFA may be one of the mechanisms regulating mitochondrial biogenesis in regenerating skeletal muscle. Taken together, our results suggest that mitochondrial biogenesis may be an important regulatory event during muscle regeneration.

scholarly journals Dynamic Expression and the Role of BDNF in Exercise-induced Skeletal Muscle Regeneration

2017 ◽  
Vol 38 (13) ◽  
pp. 959-966 ◽  
Author(s):  
Tao Yu ◽  
Yun Chang ◽  
Xiao Gao ◽  
Han Li ◽  
Peng Zhao
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Mrna Level ◽  
Elevated Serum ◽  
Skeletal Muscle Regeneration ◽  
Sprague Dawley ◽  
Bdnf Mrna ◽  
Post Exercise ◽  
Downhill Running ◽  
Exercise Induced

AbstractBrain-derived neurotrophic factor (BDNF) is a myokine. However, its role in skeletal muscle has not been well elucidated. In this study, we aimed to investigate its expression profile in skeletal muscle following downhill running and to explore its functions. Male Sprague Dawley rats were assigned to sedentary and downhill running groups. Tail vein blood, total mRNA and protein from soleus muscle was obtained from rats at different time points post-exercise (1d, 3d, 5d, 7d and 14d). We found a significant elevation of BDNF mRNA level 5d and 7d post-exercise (p<0.05), increased BDNF protein level 1d, 3d, 7d and 14d post-exercise (p<0.05), and continuously elevated serum BDNF level (p<0.05). In addition, serum creatine kinase activity was increased 5d following exercise (p<0.05); expression of MyoD was elevated (p<0.05); disruption of myofibers and centralized nuclei in damaged myofibers were clearly observed 1d and 5d post-exercise, respectively. Moreover, AMPK phosphorylation was present 1d post-exercise (p<0.05), while AKT was phosphorylated for 5d post-exercise (p<0.05). In conclusion, downhill running induces a time-dependent up-regulation of BDNF in skeletal muscle, which is involved in exercise-induced skeletal muscle regeneration.

scholarly journals RNU (Foxn1RNU-Nude) Rats Demonstrate an Improved Ability to Regenerate Muscle in a Volumetric Muscle Injury Compared to Sprague Dawley Rats

2021 ◽  
Vol 8 (1) ◽  
pp. 12
Author(s):  
Michael J. McClure ◽  
Lucas C. Olson ◽  
David J. Cohen ◽  
Yen Chen Huang ◽  
Shirley Zhang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Muscle Force ◽  
Immune Cell ◽  
Fiber Formation ◽  
Skeletal Muscle Regeneration ◽  
Host Responses ◽  
Sprague Dawley ◽  
Sd Rats ◽  
Fiber Number

Products developed for skeletal muscle regeneration frequently incorporate allogeneic and xenogeneic materials to elicit a regenerative response to heal skeletal muscle wounds. To avoid graft rejection in preclinical studies, immunodeficient rodents are used. Whether the immunodeficiency alters the host response to the material in skeletal muscle has not been studied. In this study, we hypothesized that an allogeneic acellular skeletal muscle grafts implanted in an immunodeficient rat (RNU, Foxn1-deficient) would exhibit better new muscle fiber formation compared to grafts implanted in immunocompetent Sprague Dawley (SD) rats. Decellularized SD skeletal muscle matrix (DMM) was implanted in the gastrocnemius (N = 8 rats/group). 56 days after surgery, animal gait was examined and animals were euthanized. Muscle force was assessed and fiber number as well as immune cell infiltrate was measured by histomorphometry and immunohistochemistry. Animal gait and percent recovery of muscle force were unchanged in both groups, but newly regenerated muscle fibers increased in RNU rats. Macrophage staining for CD68 was higher in RNU rats than in SD rats. These data show differences in muscle regeneration between animal models using the same biomaterial treatment, but these differences could not be ascribed to the immune response. Overall, our data provide awareness that more studies are needed to understand how host responses to biomaterials differ based on the animal model used.

PGC-1α and PGC-1β have both similar and distinct effects on myofiber switching toward an oxidative phenotype

2006 ◽  
Vol 291 (4) ◽  
pp. E807-E816 ◽  
Author(s):  
Ole Hartvig Mortensen ◽  
Lis Frandsen ◽  
Peter Schjerling ◽  
Erica Nishimura ◽  
Niels Grunnet
Keyword(s):  
Skeletal Muscle ◽  
Enzymatic Activity ◽  
Muscle Fiber ◽  
Citrate Synthase ◽  
Fiber Type ◽  
Mrna Level ◽  
Creatine Kinase Activity ◽  
Negative Regulator ◽  
Peroxisome Proliferator ◽  
Mrna Levels

Peroxisome proliferator-activated receptor-γ coactivator-1α and -1β (PGC-1α and PGC-1β) were overexpressed by adenovirus-mediated gene transfer in cultures of primary rat skeletal muscle cells derived from neonatal myoblasts. Effects on muscle fiber type transition and metabolism were studied from days 5 to 22 of culture. PGC-1α and PGC-1β overexpression caused a three- to fourfold increase in mRNA level, a doubling of enzymatic activity of citrate synthase, a slight increase in short-chain acyl-CoA dehydrogenase mRNA, a doubling of the mRNA level, and a 30–50% increase in enzymatic activity of glyceraldehyde-3-phosphate dehydrogenase. Lactate dehydrogenase or creatine kinase activity was unchanged. PGC-1α enhanced glycogen buildup twofold at 5 or 25 mM glucose, whereas PGC-1β caused a decrease. Both PGC-1α and PGC-1β overexpression caused a faster maturation of myotubes, as seen by mRNA downregulation of the immature embryonal and perinatal myosin heavy-chain (MHC) isoforms. PGC-1α or PGC-1β overexpression enhanced mRNA of the slow oxidative-associated MHC isoform MHCIb and downregulated mRNA levels of the fast glycolytic-associated MHC isoforms MHCIIX and MHCIIB. Only PGC-1β overexpression caused an increase in mRNA of the intermediary fast oxidative-associated MHC isoform MHCIIA. PGC-1α or PGC-1β overexpression upregulated GLUT4 mRNA and downregulated myocyte enhancer factor 2C transcription factor mRNA; only PGC-1α overexpression caused an increase in the mRNA expression of TRB3, a negative regulator of insulin signaling. These results show that both PGC-1α and PGC-1β are involved in the regulation of skeletal muscle fiber transition and metabolism and that they have both overlapping and differing effects.

Lack of Smad3 signaling leads to impaired skeletal muscle regeneration

2012 ◽  
Vol 303 (1) ◽  
pp. E90-E102 ◽  
Author(s):  
Xiaojia Ge ◽  
Anuradha Vajjala ◽  
Craig McFarlane ◽  
Walter Wahli ◽  
Mridula Sharma ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Mitochondrial Biogenesis ◽  
Muscle Regeneration ◽  
Intracellular Signaling ◽  
Muscle Injury ◽  
Transforming Growth Factor ◽  
Tibialis Anterior Muscle ◽  
Skeletal Muscle Regeneration ◽  
Muscle Weight

Smad3 is a key intracellular signaling mediator for both transforming growth factor-β and myostatin, two major regulators of skeletal muscle growth. Previous published work has revealed pronounced muscle atrophy together with impaired satellite cell functionality in Smad3-null muscles. In the present study, we have further validated a role for Smad3 signaling in skeletal muscle regeneration. Here, we show that Smad3-null mice had incomplete recovery of muscle weight and myofiber size after muscle injury. Histological/immunohistochemical analysis suggested impaired inflammatory response and reduced number of activated myoblasts during the early stages of muscle regeneration in the tibialis anterior muscle of Smad3-null mice. Nascent myofibers formed after muscle injury were also reduced in number. Moreover, Smad3-null regenerated muscle had decreased oxidative enzyme activity and impaired mitochondrial biogenesis, evident by the downregulation of the gene encoding mitochondrial transcription factor A, a master regulator of mitochondrial biogenesis. Consistent with known Smad3 function, reduced fibrotic tissue formation was also seen in regenerated Smad3-null muscle. In conclusion, Smad3 deficiency leads to impaired muscle regeneration, which underscores an essential role of Smad3 in postnatal myogenesis. Given the negative role of myostatin during muscle regeneration, the increased expression of myostatin observed in Smad3-null muscle may contribute to the regeneration defects.

scholarly journals Mitochondrial maintenance via autophagy contributes to functional skeletal muscle regeneration and remodeling

2016 ◽  
Vol 311 (2) ◽  
pp. C190-C200 ◽  
Author(s):  
Anna S. Nichenko ◽  
W. Michael Southern ◽  
Mark Atuan ◽  
Junna Luan ◽  
Kristen B. Peissig ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Strength ◽  
Muscle Regeneration ◽  
Citrate Synthase ◽  
Complete Recovery ◽  
Oxidative Capacity ◽  
Primary Objective ◽  
Skeletal Muscle Regeneration ◽  
Mitochondrial Enzyme ◽  
Mitochondrial Remodeling

The primary objective of this study was to determine whether alterations in mitochondria affect recovery of skeletal muscle strength and mitochondrial enzyme activity following myotoxic injury. 3-Methyladenine (3-MA) was administered daily (15 mg/kg) to blunt autophagy, and the creatine analog guanidionpropionic acid (β-GPA) was administered daily (1% in chow) to enhance oxidative capacity. Male C57BL/6 mice were randomly assigned to nontreatment (Con, n = 6), 3-MA-treated ( n = 6), and β-GPA-treated ( n = 8) groups for 10 wk. Mice were euthanized at 14 days after myotoxic injury for assessment of mitochondrial remodeling during regeneration and its association with the recovery of muscle strength. Expression of several autophagy-related proteins, e.g., phosphorylated Ulk1 (∼2- to 4-fold, P < 0.049) was greater in injured than uninjured muscles, indicating a relationship between muscle regeneration/remodeling and autophagy. By 14 days postinjury, recovery of muscle strength (18% less, P = 0.03) and mitochondrial enzyme (e.g., citrate synthase) activity (22% less, P = 0.049) were significantly lower in 3-MA-treated than Con mice, suggesting that the autophagy process plays an important role during muscle regeneration. In contrast, muscle regeneration was nearly complete in β-GPA-treated mice, i.e., muscle strength recovered to 93% of baseline vs. 78% for Con mice. Remarkably, 14 days allowed sufficient time for a near-complete recovery of mitochondrial function in β-GPA-treated mice (e.g., no difference in citrate synthase activity between injured and uninjured, P = 0.49), indicating a robust mitochondrial remodeling process during muscle regeneration. In conclusion, autophagy is likely activated following muscle injury and appears to play an important role in functional muscle regeneration.

scholarly journals Expression of Glucocorticoid Receptors in the Regenerating Human Skeletal Muscle

2011 ◽  
pp. S147-S154
Author(s):  
D. FILIPOVIĆ ◽  
S. PIRKMAJER ◽  
K. MIS ◽  
T. MARS ◽  
Z. GRUBIC
Keyword(s):  
Skeletal Muscle ◽  
Muscle Regeneration ◽  
Human Skeletal Muscle ◽  
Glucocorticoid Receptors ◽  
Mrna Level ◽  
Skeletal Muscle Regeneration ◽  
Major Player ◽  
Mrna And Protein Expression ◽  
Basic Characteristics ◽  
Cellular Responsiveness

Many stress conditions are accompanied by skeletal muscle dysfunction and regeneration, which is essentially a recapitulation of the embryonic development. However, regeneration usually occurs under conditions of hypothalamus-pituitary-adrenal gland axis activation and therefore increased glucocorticoid (GC) levels. Glucocorticoid receptor (GR), the main determinant of cellular responsiveness to GCs, exists in two isoforms (GRα and GRβ) in humans. While the role of GRα is well characterized, GRβ remains an elusive player in GC signalling. To elucidate basic characteristics of GC signalling in the regenerating human skeletal muscle we assessed GRα and GRβ expression pattern in cultured human myoblasts and myotubes and their response to 24-hour dexamethasone (DEX) treatment. There was no difference in GRα mRNA and protein expression or DEX-mediated GRα down-regulation in myoblasts and myotubes. GRβ mRNA level was very low in myoblasts and remained unaffected by differentiation and/or DEX. GRβ protein could not be detected. These results indicate that response to GCs is established very early during human skeletal muscle regeneration and that it remains practically unchanged before innervation is established. Very low GRβ mRNA expression and inability to detect GRβ protein suggests that GRβ is not a major player in the early stages of human skeletal muscle regeneration.

Endurance training increases skeletal muscle LKB1 and PGC-1α protein abundance: effects of time and intensity

2005 ◽  
Vol 289 (6) ◽  
pp. E960-E968 ◽  
Author(s):  
Eric B. Taylor ◽  
Jeremy D. Lamb ◽  
Richard W. Hurst ◽  
David G. Chesser ◽  
William J. Ellingson ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Endurance Training ◽  
Time Course ◽  
Citrate Synthase ◽  
Interval Training ◽  
Training Data ◽  
Peroxisome Proliferator ◽  
Sprague Dawley ◽  
Hexokinase Ii ◽  
Training Time

Recent research suggests that LKB1 is the major AMP-activated protein kinase kinase (AMPKK). Peroxisome-proliferator-activated receptor-γ coactivator-1α (PGC-1α) is a master coordinator of mitochondrial biogenesis. Previously we reported that skeletal muscle LKB1 protein increases with endurance training. The purpose of this study was to determine whether training-induced increases in skeletal muscle LKB1 and PGC-1α protein exhibit a time course and intensity-dependent response similar to that of citrate synthase. Male Sprague-Dawley rats completed endurance- and interval-training protocols. For endurance training, rats trained for 4, 11, 25, or 53 days. Interval-training rats trained identically to endurance-trained rats, except that after 25 days interval training was combined with endurance training. Time course data were collected from endurance-trained red quadriceps (RQ) after each time point. Interval training data were collected from soleus, RQ, and white quadriceps (WQ) muscle after 53 days only. Mouse protein 25 (MO25) and PGC-1α protein increased significantly after 4 days. Increased citrate synthase activity, increased LKB1 protein, and decreased AMPKK activity were found after 11 days. Maximal increases occurred after 4 days for hexokinase II, 25 days for MO25, and 53 days for citrate synthase, LKB1, and PGC-1α. In WQ, but not RQ or soleus, interval training had an additive effect to endurance training and induced significant increases in all proteins measured. These results demonstrate that LKB1 and PGC-1α protein abundances increase with endurance and interval training similarly to citrate synthase. The increase in LKB1 and PGC-1α with endurance and interval training may function to maintain the training-induced increases in mitochondrial mass.

Myogenic and nonmyogenic cells differentially express proteinases, Hsc/Hsp70, and BAG-1 during skeletal muscle regeneration

2003 ◽  
Vol 285 (1) ◽  
pp. E206-E215 ◽  
Author(s):  
Stéphanie Duguez ◽  
Marie-Catherine Le Bihan ◽  
Dominique Gouttefangeas ◽  
Léonard Féasson ◽  
Damien Freyssenet
Keyword(s):  
Skeletal Muscle ◽  
Heat Shock ◽  
Time Course ◽  
Immunohistochemical Analysis ◽  
Inflammatory Cells ◽  
Skeletal Muscle Regeneration ◽  
Nuclear Antigen ◽  
Strongly Correlated ◽  
Sprague Dawley ◽  
Sprague Dawley Rats

Skeletal muscle has a remarkable capacity to regenerate after injury. To determine whether changes in the expression of proteinases, 73-kDa constitutive heat shock cognate protein (Hsc70) and stress-inducible 72-kDa heat shock protein (Hsp70) (Hsc/Hsp70), and Bcl-2-associated gene product-1 (BAG-1) contribute to the remodeling response of muscle tissue, tibialis anterior muscles of male Sprague-Dawley rats were injected with 0.75% bupivacaine and removed at 3, 5, 7, 10, 14, 21, or 35 days postinjection ( n = 5–7/group). The immunohistochemical analysis of desmin, α-actin, and developmental/neonatal myosin heavy chain expressions indicated the presence of myoblasts ( days 3–7), inflammatory cells ( days 3–7), degenerating myofibers ( days 3–7), regenerating myofibers ( days 5–10), and growing mature myofibers ( days 10–21) in regenerating muscles. Our biochemical analysis documented profound adaptations in proteolytic metabolism characterized by significant increases in the enzyme activities of matrix metalloproteinases 2 and 9 and plasminogen activators ( days 3–14), calpains 1 and 2 ( days 3–7), cathepsins B and L( days 3–10), and proteasome ( days 3–14). Proteasome activity was strongly correlated with proliferating cell nuclear antigen protein level, suggesting that proteasome played a key role in myoblast proliferation. The expression pattern of BAG-1, a regulatory cofactor of Hsc/Hsp70 at the interface between protein folding and proteasomal proteolysis, did not corroborate the changes in proteasome enzyme activity, suggesting that BAG-1 may promote other functions, such as the folding capacity of Hsc/Hsp70. Altogether, the diversity of functions attributed to proteinases in the present study was strongly supported by the relative changes in the proportion of myogenic and nonmyogenic cells over the time course of regeneration.

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