Myostatin deficiency blunts mechanical adaptation of soleus muscle to overload.

Skeletal Muscle-Specific Ablation of raptor, but Not of rictor, Causes Metabolic Changes and Results in Muscle Dystrophy

Decision letter: Altered regulation of Ia afferent input during voluntary contraction in humans with spinal cord injury

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Skeletal muscle hypertrophy requires the co-ordinated expression of locally acting growth factors that promote myofibre growth and concurrent adaptive changes in the microvasculature. These studies tested the hypothesis that vascular endothelial growth factor (VEGF) and heparin-binding epidermal growth factor (HB-EGF) expression are upregulated during the early stages of compensatory muscle growth induced by chronic functional overload (FO). Bilateral FO of the plantaris and soleus muscles was induced for 3 or 7 days in the hindlimbs of adult female Sprague-Dawley rats (n = 5 per group) and compared with control (non-FO) rats. Relative muscle mass (in mg (kg body weight)(-1)) increased by 18 and 24% after 3 days and by 20 and 33% after 7 days in the plantaris and soleus muscles, respectively. No differences in HB-EGF mRNA or protein were observed in either muscle of FO rats relative to control muscles. The VEGF mRNA was similar in the soleus muscles of FO and control rats, whereas a significant elevation occurred at 3 and 7 days of FO in the plantaris muscle. However, VEGF protein expression after 3 days of FO exhibited a differential response; expression in the soleus muscle decreased 1.6-fold, whereas that in the plantaris muscle increased 1.8-fold compared with the control muscle. After 7 days of FO, VEGF protein remained elevated within the plantaris muscle, but returned to basal levels in the soleus. Robust basal HB-EGF and VEGF protein expression was consistently seen in control muscles. In all groups, immunohistochemistry for VEGF protein displayed a distinct striated expression pattern within myofibres, with considerably less labelling in extracellular spaces. Constitutive expression of HB-EGF and VEGF in control myofibres is consistent with housekeeping roles for these growth factors in skeletal muscle tissue. However, the specific patterns of VEGF expression in these muscles during FO may reflect the chronic changes in neural recruitment between muscles and the co-ordination of angiogenic and/or other hypertrophic responses.

Vitamin D Increases Cellular Turnover and Functionally Restores the Skeletal Muscle after Crush Injury in Rats

Effects of mechanical loading on the expression level of tripartite motif‐containing 72 (TRIM72) and caveolin‐3 (Cav‐3) in mouse soleus muscle were investigated. Mice were subjected to (1) continuous hindlimb suspension (HS) for 2 weeks followed by 1‐week ambulation recovery or (2) functional overloading (FO) on the soleus by cutting the distal tendons of the plantaris and gastrocnemius muscles. Soleus muscle atrophy was induced by 2‐week hindlimb suspension (HS). Reloading‐associated regrowth of atrophied soleus muscle was observed by 1‐week reloading following HS. HS also depressed the expression level of insulin receptor substrate‐1 (IRS‐1) mRNA, TRIM72, Cav‐3, and phosphorylated Akt (p‐Akt)/total Akt (t‐Akt), but increased the phosphorylated level of p38 mitogen‐activated protein kinase (p‐p38MAPK) in soleus muscle. Thereafter, the expression level of MyoD mRNA, TRIM72 (mRNA, and protein), and Cav‐3 was significantly increased and recovered to the basal level during 1‐week reloading after HS. Although IRS‐1 expression was also upregulated by reloading, the expression level was significantly lower than that before HS. Significant increase in p‐Akt and phosphorylated p70 S6 kinase (p‐p70S6K) was observed by 1‐day reloading. On the other hand, 1‐week functional overloading (FO) induced soleus muscle hypertrophy. In FO‐associated hypertrophied soleus muscle, the expression level of IRS‐1 mRNA, MyoD mRNA, TRIM72 mRNA, p‐Akt, and p‐p70S6K was increased, but the expression of Cav‐3 and p‐p38MAPK was decreased. FO had no effect on the protein expression level of TRIM72. These observations suggest that the loading‐associated upregulation of TRIM72 protein in skeletal muscle may depress the regrowth of atrophied muscle via a partial suppression of IRS‐1. In addition, downregulation of Cav‐3 in skeletal muscle may depress overloading‐induced muscle hypertrophy.

Myofiber size is dynamically regulated, increasing and decreasing depending on muscle use. Hypertrophy is defined by increases in myofiber cross-sectional area and mass as well as myofibrillar protein content. Myofibers contain many hundreds of nuclei, each of which has a nuclear domain. A nuclear

The aim of the study was to investigate if myostatin dysfunction would promote the gain in muscle mass and peak isometric force (P0 ) of soleus muscle (SOL) in response to functional overloading (FO) after ablation of the gastrocnemius muscle. Fifteen male Berlin high (BEH) mice homozygous for the compact mutation causing dysfunction of myostatin and 17 mice with the corresponding wild-type allele (BEH+/+) were subjected to FO of SOL for 28 days at the age of 14 weeks. Compared with BEH+/+ mice, SOL of BEH was heavier (mean ± SD, 13.5 ± 1.5 vs 21.4 ± 1.8 mg, respectively, P < 0.001). After FO, SOL mass increased relatively more in BEH+/+ than BEH strain (34.9 ± 11.5 vs 17.7 ± 11.9%, respectively, P < 0.01). P0 fell (P < 0.01) only in BEH strain, which also showed an increase (P < 0.01) in optimal muscle length. Specific P0 became even more depressed in BEH compared with BEH+/+ strain (8.4 ± 1.4 vs 10.8 ± 1.3 N/g, respectively, P < 0.001). Phosphorylation p70 S6 kinase did not differ between the strains. In summary, myostatin dysfunction impairs adaptation of SOL muscle to high functional demands.

To determine the level of coordination in succinate dehydrogenase (SDH) activity between plantaris motoneurons and muscle fibers, the soleus and gastrocnemius muscles were bilaterally excised in four cats to subject the plantaris to functional overload (FO). Five normal cats served as controls. Twelve weeks after surgery the right plantaris in each cat was injected with horseradish peroxidase to identify plantaris motoneurons. SDH activity then was measured in a population of plantaris motoneurons and muscle fibers in each cat. Control motoneurons and muscle fibers had similar mean SDH activities and a similar relationship between cell size and SDH activity. After FO, muscle fiber size doubled and mean muscle fiber SDH activity halved. Motoneuron mean SDH activity and size were unaffected by FO. Total SDH activity was unchanged in both the motoneurons and muscle fibers after FO. These changes suggest a selective increase in contractile proteins with little or no modulation of mitochondrial proteins in the muscle fibers, because total SDH activity was unchanged in muscle fibers after FO. These data demonstrate that although mean SDH activities were similar in control motoneurons and muscle fibers, mean SDH activities in these two cell types can change independently.

The purpose of this study was to determine the effects of functional overload (FO) combined with growth hormone/insulin-like growth factor I (GH/IGF-I) administration on myonuclear number and domain size in rat soleus muscle fibers. Adult female rats underwent bilateral ablation of the plantaris and gastrocnemius muscles and, after 7 days of recovery, were injected three times daily for 14 days with GH/IGF-I (1 mg/kg each; FO + GH/IGF-I group) or saline vehicle (FO group). Intact rats receiving saline vehicle served as controls (Con group). Muscle wet weight was 32% greater in the FO than in the Con group: 162 +/- 8 vs. 123 +/- 16 mg. Muscle weight in the FO + GH/IGF-I group (196 +/- 14 mg) was 59 and 21% larger than in the Con and FO groups, respectively. Mean soleus fiber cross-sectional area of the FO + GH/IGF-I group (2,826 +/- 445 microm2) was increased compared with the Con (2,044 +/- 108 microm2) and FO (2,267 +/- 301 microm2) groups. The difference in fiber size between the FO and Con groups was not significant. Mean myonuclear number increased in FO (187 +/- 15 myonuclei/mm) and FO + GH/IGF-I (217 +/- 23 myonuclei/mm) rats compared with Con (155 +/- 12 myonuclei/mm) rats, although the difference between FO and FO + GH/IGF-I animals was not significant. The mean cytoplasmic volume per myonucleus (myonuclear domain) was similar across groups. These results demonstrate that the larger mean muscle weight and fiber cross-sectional area occurred when FO was combined with GH/IGF-I administration and that myonuclear number increased concomitantly with fiber volume. Thus there appears to be some mechanism(s) that maintains the myonuclear domain when a fiber hypertrophies.

The consequences of two-week hindlimb suspension (HS) on skeletal muscle atrophy were investigated in balanced diet-fed Fat-1 transgenic and C57BL/6 wild-type mice. Body composition and gastrocnemius fatty acid composition were measured. Skeletal muscle force, cross-sectional area (CSA), and signaling pathways associated with protein synthesis (protein kinase B, Akt; ribosomal protein S6, S6, eukaryotic translation initiation factor 4E-binding protein 1, 4EBP1; glycogen synthase kinase3-beta, GSK3-beta; and extracellular-signal-regulated kinases 1/2, ERK 1/2) and protein degradation (atrophy gene-1/muscle atrophy F-box, atrogin-1/MAFbx and muscle RING finger 1, MuRF1) were evaluated in the soleus muscle. HS decreased soleus muscle wet and dry weights (by 43% and 26%, respectively), muscle isotonic and tetanic force (by 29% and 18%, respectively), CSA of the soleus muscle (by 36%), and soleus muscle fibers (by 45%). Fat-1 transgenic mice had a decrease in the ω-6/ω-3 polyunsaturated fatty acids (PUFAs) ratio as compared with C57BL/6 wild-type mice (56%, p < 0.001). Fat-1 mice had lower soleus muscle dry mass loss (by 10%) and preserved absolute isotonic force (by 17%) and CSA of the soleus muscle (by 28%) after HS as compared with C57BL/6 wild-type mice. p-GSK3B/GSK3B ratio was increased (by 70%) and MuRF-1 content decreased (by 50%) in the soleus muscle of Fat-1 mice after HS. Balanced diet-fed Fat-1 mice are able to preserve in part the soleus muscle mass, absolute isotonic force and CSA of the soleus muscle in a disuse condition.

5. During the step cycle the peaks of both MG and SOL force profiles occur before the end of the yield (E2) phase, as both muscles undergo active lengthening. In contrast, peak MG and SOL forces during vertical jumping coincide with the end of active lengthening and the onset of ankle extensor shortening. 6. The results are consistent with the hypothesis that the inherent stiffness of active muscle during the step cycle is an important factor in the control of force output from hindlimb extensor muscles in locomotion. The division of labor between MG and SOL and the absolute force levels required from the MG during the full range of hindlimb movements in posture, locomotion, and jumping appear to be precisely matched to the very different characteristics of the motor-unit populations composing these synergistic muscles.

Does obesity reduce load-induced muscle hypertrophy?

Diabetes was produced by withholding insulin treatment from previously alloxanized female rats. Isometric contraction was assessed in soleus and extensor digitorum longus (EDL) muscles removed 2 h to 32 days after insulin withdrawal. Directly induced contractions were measured in vitro at 20 degrees C. In soleus muscles from severely diabetic rats, average twitch and tetanic forces were normal or slightly greater than that of controls of similar age, whereas in EDL, marked decreases appeared in both twitch and tetanic forces. Soleus muscle from severely diabetic rats was not depolarized as already reported in EDL. After 16 and 32 days in the diabetic state, soleus muscles from moderately diabetic rats generated average tetanic forces that were equal to that found in age-matched controls, whereas EDL tetanic forces were significantly (P = less than 0.01) weaker. Average specific twitch force in diabetic soleus muscles was greater than age-matched controls after 16 and 32 days in the diabetic state. In diabetic soleus muscle, significant increases in the average half relaxation time and twitch duration were seen after prolonged (16 and 32 days) periods of diabetes. No changes were seen in the same temporal parameters of the twitch in diabetic EDL muscle. A greater atrophy appeared in EDL than in soleus after 16 and 32 days of uncontrolled diabetes.

The aim of this study was to evaluate the effect of overload-induced hypertrophy on extensor digitorum longus (EDL) and soleus muscles of streptozotocin-induced diabetic rats. The overload-induced hypertrophy and absolute tetanic and twitch forces increases in EDL and soleus muscles were not different between diabetic and control rats. Phospho-Akt and rpS6 contents were increased in EDL muscle after 7 days of overload and returned to the pre-overload values after 30 days. In the soleus muscle, the contents of total and phospho-Akt and total rpS6 were increased in both groups after 7 days. The contents of total Akt in controls and total rpS6 and phospho-Akt in the diabetic rats remained increased after 30 days. mRNA expression after 7 days of overload in the EDL muscle of control and diabetic animals showed an increase in MGF and follistatin and a decrease in myostatin and Axin2. The expression of FAK was increased and of MuRF-1 and atrogin-1 decreased only in the control group, whereas Ankrd2 expression was enhanced only in diabetic rats. In the soleus muscle caused similar changes in both groups: increase in FAK and MGF and decrease in Wnt7a, MuRF-1, atrogin-1, and myostatin. Differences between groups were observed only in the increased expression of follistatin in diabetic animals and decreased Ankrd2 expression in the control group. So, insulin deficiency does not impair the overload-induced hypertrophic response in soleus and EDL muscles. However, different mechanisms seem to be involved in the comparable hypertrophic responses of skeletal muscle in control and diabetic animals.