Recovery of strength is dependent on mTORC1 signaling after eccentric muscle injury

Introduction: Eccentric contractions may cause immediate and long‐term reductions in muscle strength that can be recovered through increased protein synthesis rates. The purpose of this study was to determine whether the mechanistic target‐of‐rapamycin complex 1 (mTORC1), a vital controller of protein synthesis rates, is required for return of muscle strength after injury. Methods: Isometric muscle strength was assessed before, immediately after, and then 3, 7, and 14 days after a single bout of 150 eccentric contractions in mice that received daily injections of saline or rapamycin. Results: The bout of eccentric contractions increased the phosphorylation of mTORC1 (1.8‐fold) and p70s6k1 (13.8‐fold), mTORC1's downstream effector, 3 days post‐injury. Rapamycin blocked mTORC1 and p70s6k1 phosphorylation and attenuated recovery of muscle strength (～20%) at 7 and 14 days. Conclusion: mTORC1 signaling is instrumental in the return of muscle strength after a single bout of eccentric contractions in mice. Muscle Nerve 54 : 914–924, 2016     

Evidence of mdx mouse skeletal muscle fragility in vivo by eccentric running exercise

Duchenne muscular dystrophy is an X-linked devastating disease due to the lack of expression of a functional dystrophin. Unfortunately, the dystrophin-deficient mdx mouse model does not present clinical signs of dystrophy before the age of 18 months, and the role of dystrophin in fiber integrity is not fully understood. The fragility of the skeletal muscle fibers was investigated in transgenic mice expressing β-galactosidase under the control of a muscle specific promoter. Adult mdx/β-galactosidase (dystrophin-negative) and normal/β-galactosidase (dystrophin-positive) mice were submitted to one short session of eccentric, downhill running exercise. The leakage of muscle enzymes creatine kinase and β-galactosidase was investigated before, 1 h after, and 3 days after the running session. A significant and transient rise in the level of these enzymes was noted in the serum of mdx mice following the exercise session. Thus, the lack of dystrophin in the mdx model led to local microdamages to the exercised muscle allowing leakage of proteins from the fibers. The peak leakage was transient, suggesting that muscle fiber lesions were rapidly repaired following this short, noninvasive eccentric running session. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:567–576, 1998.     

Heart rate recovery after exercise is associated with resting QTc interval in young men

Heart rate recovery (HRR) after exercise and spectral decomposition of heart rate variability (HRV), measures of autonomic nervous system function, are predictors of cardiovascular morbidity/mortality. QT interval, an index of ventricular depolarization and repolarization attained from surface ECG, is also associated with morbidity/mortality and is strongly influenced by autonomic tone. The purpose of this study was to assess the association between HRR after exercise, resting HRV and resting rate corrected QT interval in young healthy men. HRR was assessed in 37 men (23.3 ± 0.6 years) 1 minute after a graded exercise test. Resting QT interval was derived from ECG recordings and rate corrected using five formulae (Bazett, Fridericia, Hodges, Framingham, and the nomogram method of Karjalainen). Resting HRV was spectrally decomposed using an autoregressive approach. A negative correlation was detected for QTc interval and HRR for each method (r = −0.36 to −0.48, P < 0.05). There was no correlation between high frequency power of HRV (a marker of parasympathetic modulation) and QTc interval. There was a negative relationship between absolute LF power (a marker of both sympathetic and parasympathetic modulation) and QTc interval for Karjalainen, Framingham, and Bazett correction methods (r = −0.33 to −0.47, P < 0.05). Resting LF power of HRV and HRR after exercise are inversely associated with resting QTc interval in young healthy men, supporting a relationship between cardiac autonomic nervous system function and ventricular depolarization and repolarization.     

热应激预处理对离心运动大鼠骨骼肌自由基代谢的影响

背景：研究表明热预处理能够提高肌肉抗损伤的能力,但具体的机制尚不清楚。目的：观察热应激预处理对离心运动大鼠骨骼肌超氧化物歧化酶活性及丙二醛含量的影响。方法：雄性Wistar大鼠随机分为对照组、离心运动组、预热应激+离心运动组。热应激温度为43 ℃,时间约35 min。采用-16°下坡跑台跑做大负荷间歇性离心运动,跑速为26.8 m/min,运动5 min,间歇1 min,共进行10组。分别于运动前1 h、运动后1,24,48 h取大鼠腓肠肌,采用硫代巴比妥酸法测定大鼠丙二醛含量,黄嘌呤氧化酶法测定超氧化物歧化酶活性。结果与结论：与对照组比较,离心运动组大鼠腓肠肌丙二醛含量显著增高(P < 0.05),并随运动后时间的延长逐渐升高,超氧化物歧化酶活性随运动后时间的延长显著降低(P < 0.05)。与离心运动组比较,预热应激+离心运动组大鼠腓肠肌超氧化物歧化酶活性显著增高(P < 0.05),丙二醛含量显著降低(P < 0.05)。说明热应激预处理可增强骨骼肌超氧化物歧化酶活性,降低丙二醛含量,对离心运动损伤有保护作用。     

Forced exercise does not improve recovery after hemorrhagic stroke in rats

Exercise can improve recovery following ischemia and intracerebral hemorrhage (ICH) in rodents. We tested whether forced exercise (EX; running wheel) prior to and/or following ICH in rats would reduce lesion volume and improve functional outcome (walking, skilled reaching, spontaneous paw usage) at 7 weeks post-ICH. A striatal hemorrhage was produced by infusing collagenase. First, we compared animals that received EX (2 weeks; 1 h/day) ending two days prior to ICH and/or starting two weeks following ICH. EX did not improve functional recovery or affect lesion size. Doubling the amount of EX given per day (two 1-h sessions) both prior to and following ICH did not alter lesion volume, but worsened recovery. We then determined if EX (1 h/day) prior to and following ICH would affect outcome after a somewhat milder insult. There were no differences between the groups in lesion volume or recovery. Finally, we used a hemoglobin assay at 12 h following ICH to determine if pre-stroke EX (2 weeks; 1 h/day) aggravated bleeding. It did not. These observations suggest that EX does not improve outcome when given prior to and/or when delayed following ICH. Effective rehabilitation for ICH will likely require more complex interventions than forced running.     

Creatine monohydrate supplementation does not increase muscle strength, lean body mass, or muscle phosphocreatine in patients with myotonic dystrophy type 1

Creatine monohydrate (CrM) supplementation may increase strength in some types of muscular dystrophy. A recent study in myotonic muscular dystrophy type 1 (DM1) did not find a significant treatment effect, but measurements of muscle phosphocreatine (PCr) were not performed. We completed a randomized, double-blind, cross-over trial using 34 genetically confirmed adult DM1 patients without significant cognitive impairment. Participants received CrM (5 g, approximately 0.074 g/kg daily) and a placebo for each 4-month phase with a 6-week wash-out. Spirometry, manual muscle testing, quantitative isometric strength testing of handgrip, foot dorsiflexion, and knee extension, handgrip and foot dorsiflexion endurance, functional tasks, activity of daily living scales, body composition (total, bone, and fat-free mass), serum creatine kinase activity, serum creatinine concentration and clearance, and liver function tests were completed before and after each intervention, and muscle PCr/beta-adenosine triphosphate (ATP) ratios of the forearm flexor muscles were completed at the end of each phase. CrM supplementation did not increase any of the outcome measurements except for plasma creatinine concentration (but not creatinine clearance). Thus, CrM supplementation at 5 g daily does not have any effects on muscle strength, body composition, or activities of daily living in patients with DM1, perhaps because of a failure of the supplementation to increase muscle PCr/beta-ATP content.     

Cerebral autoregulation is temporarily disturbed in the early recovery phase after dynamic resistance exercise

Abstract Aim To determine cerebral blood-flow velocity (CBFV) and parameters of dynamic cerebral autoregulation (CA) during and after exhausting resistance exercise. Methods Strength endurance (23 repetitions) and maximal strength training (8 repetitions) in 16 female and 16 male athletes on a leg curler (m. quadriceps training; approx. 2 s contraction) in the upright position. Registration of ECG, blood pressure by Finapres^®, CBFV by transcranial Doppler (TCD), and breathing by a Zak^® breathing-belt. Additional repetitive ergospirometry (O₂-uptake, CO₂-elimination, ventilation) and blood gas analyses were performed in a subgroup of seven athletes. From BP and CBFV cerebrovascular resistance (CVR), pulsatility index (PI) as well as LF-power, gain and phase-angle (frequency analysis) were derived. Results All athletes showed significant (p<0.01) 15 % to 30 % increases in CBFV during both training sets without signs of flow depression due to Valsalva maneuvers. In the early recovery, when blood pressure rapidly decreased, CBFV amplitude significantly (p<0.01) increased for 60–80 seconds with mean flow (Vm) at the exercise level, while CVR and PI showed conflicting results, similar to a presyncopal reaction. Ergospirometry and blood gas analyses revealed no evidence of major changes in pCO₂, but phase angle was reduced (p<0.001) after exercise, together with an LF power increase (p<0.001). Conclusion An unexpected increase in CBFV amplitude and in Vm occurs directly after dynamic resistance exercise without increased pCO₂, which is comparable to a maximum leg press with hypercapnia. CVR and PI results as well as data from frequency analysis show similarities to presyncopal reactions, on the one hand, and point towards a temporarily disturbed cerebral autoregulation, on the other.     

白藜芦醇对离心运动后骨骼肌微损伤的修复

背景：白藜芦醇是一种天然的抗氧化剂和自由基廓清剂,具有清除自由基、减轻脂质过氧化等重要药理作用,目前有关白藜芦醇在减轻骨骼肌损伤、促进损伤修复方面的研究尚不多见。 目的：观察白藜芦醇对离心运动后骨骼肌超微结构损伤、血清丙二醛和肌细胞浆Ca2+浓度的影响。 设计、时间及地点：对照观察动物实验,于2007-08/2008-06在南方医科大学完成。 材料：成年雄性SD大鼠72只,实验室适应性喂养3 d后随机分为蒸馏水组(n=40)、白藜芦醇组(n=32)。白藜芦醇制剂购自湖南省洪江华光生物有限公司。 方法：白藜芦醇组大鼠每日腹腔注射1次白藜芦醇制剂60 mg/kg,蒸馏水组大鼠腹腔注射等量蒸馏水,连续2周。2周后,将大鼠在动物跑台上进行一次性下坡跑运动,速度为16 m/min,下坡坡度为16°,5 min运动,2 min休息,总运动时间为120 min。运动过程中采用人工驱赶和声刺激,不使用电刺激。 主要观察指标：于运动前、运动后即刻、运动后24,48,72 h电镜下观察比目鱼肌纤维Z线,TAB法测定血清丙二醛和流式细胞仪检测肌细胞浆Ca2+浓度。 结果：与蒸馏水组比较,白藜芦醇组镜下肌纤维损伤程度减轻,骨骼肌细胞Z线异常百分率在运动后即刻、运动后24,48,72 h比蒸馏水组分别降低了50.34%,52.67%,52.65%和53.26%(P < 0.05),离心运动引起的血清丙二醛升高程度分别下降了27.7%,29.56%,34.38%和27.79%(P < 0.05),胞浆Ca2+浓度分别降低了27.53%,25.84%,22.14%和11.62% (P < 0.05)。 结论：白藜芦醇可降低离心运动后血清丙二醛浓度和肌细胞浆Ca2+浓度,减轻运动导致的肌肉损伤。     

Heart rate recovery after exercise and incidence of type 2 diabetes in men

Objectives  We tested that slow heart rate recovery (HRR) after exercise testing, indicative of decreased parasympathetic nervous system activity, is associated with the development of type 2 diabetes in 1,813 healthy men. Methods  Heart rate recovery was calculated as the difference between maximum heart rate during the exercise test and heart rate 1 min after cessation of the exercise test. Results  During an average of 6.4 years of follow-up, 64 (3.5%) subjects developed type 2 diabetes. The unadjusted relative risk (RR) of developing incident diabetes in the slowest versus the fastest HRR quartile was 3.13 (95% CI, 1.28–7.65). However, the association was no longer significant after adjustment for diabetes risk factors and baseline glucose (RR = 2.28, 95% CI, 0.87–5.95). Conclusion  Slow HRR is associated with the development of type 2 diabetes, but these relationships were largely explained by baseline fasting glucose in healthy men.     

Short-term unilateral resistance training affects the agonist-antagonist but not the force-agonist activation relationship

In this study we investigated the contribution of neural adaptations to strength changes after 4 weeks of unilateral isometric resistance training. Maximal and submaximal isometric knee extension contractions were assessed before and after training. Surface electromyography (EMG) data were collected from the agonist and antagonist muscles and normalized to evoked maximal M-wave and maximal knee flexor EMG, respectively. The interpolated twitch technique (ITT) was also used to determine activation at maximum voluntary force (MVF). MVF increased in the trained (+20%) and untrained (+8%) legs. Agonist EMG at MVF increased in the trained leg (+26%), although activation determined via the ITT was unchanged. In both legs the position of the force-agonist EMG relationship was unchanged, but antagonist coactivation was lower for all levels of agonist activation. Strength gains in the trained leg were due to enhanced agonist activation, whereas decreased coactivation may have affected strength changes in both legs.     

Transplantation of cryopreserved human umbilical cord blood mononuclear cells does not induce sustained recovery after experimental stroke in spontaneously hypertensive rats

Previous studies have highlighted the enormous potential of cell-based therapies for stroke not only to prevent ischemic brain damage, but also to amplify endogenous repair processes. Considering its widespread availability and low immunogenicity human umbilical cord blood (HUCB) is a particularly attractive stem cell source. Our goal was to investigate the neurorestorative potential of cryopreserved HUCB mononuclear cells (MNC) after permanent middle cerebral artery occlusion (MCAO) in spontaneously hypertensive rats (SHR). Human umbilical cord blood MNC or vehicle solution was administered intravenously 24 hours after MCAO. Experimental groups were as follows: (1) quantitative polymerase chain reaction (PCR) of host-derived growth factors up to 48 hours after stroke; (2) immunohistochemical analysis of astroglial scarring; (3) magnetic resonance imaging (MRI) and weekly behavioral tests for 2 months after stroke. Long-term functional outcome and lesion development on MRI were not beneficially influenced by HUCB MNC therapy. Furthermore, HUCB MNC treatment did not change local growth factor levels and glial scarring extent. In summary, we could not demonstrate neurorestorative properties of HUCB MNC after stroke in SHR. Our results advise caution regarding a prompt translation of cord blood therapy into clinical stroke trials as long as deepened knowledge about its precise modes of action is missing.     

The association of heart rate recovery immediately after exercise with coronary artery calcium: the coronary artery risk development in young adults study

We tested whether slower heart rate recovery (HRR) following graded exercise treadmill testing (GXT) was associated with the presence of coronary artery calcium (CAC). Participants (n = 2,648) ages 18–30 years at baseline examination underwent GXT, followed by CAC screening 15 years later. Slow HRR was not associated with higher odds of testing positive (yes/no) for CAC at year 15 (OR = 0.99, p = 0.91 per standard deviation change in HRR). Slow HRR in young adulthood is not associated with the presence of CAC at middle age.     

Cerebral plasticity and recovery of function after childhood prefrontal cortex damage

Objective: Recovery of function after early brain injury depends upon both reparative and compensatory processes that are minimally understood. Using functional magnetic resonance imaging (fMRI), this study investigated the reorganization of hemispheric brain activity of a 24 year old male who suffered right prefrontal cortex damage at 7 years of age related to ruptured arteriovenous malformation. His pattern of recovery has been examined and tracked over the past 17 years and evolved from initial significant impairments in executive, spatial and attentional abilities from the brain lesion to remarkable recovery of function.

Methods: High field fMRI studies were completed with experimental cognitive tasks sensitive to right prefrontal functions, including visuospatial relational reasoning, spatial working memory, go no-go, emotional face recognition, and coin calculation. Results were compared to a matched control group for total hemispheric activity patterns.

Results: Analyses revealed that on fMRI activation tasks where the patient scored similar to controls, he activated a broader network of bilateral cortical regions than controls. On tasks where he scored lower than controls, there was under-activation of prefrontal cortical regions in comparison to controls.

Conclusion: Recovery of function after prefrontal cortex damage in childhood can occur and be associated with significant functional reorganization of hemispheric activity patterns (i.e. developmental cerebral plasticity). Although not all tasks showed recovery to the same extent in this case, those tasks with the most robust recovery entailed compensatory activation of additional cortical regions on fMRI. Further studies are needed to confirm and extend these findings.     

Post-lesion administration of the NMDA receptor antagonist MK-801 does not impair motor recovery after unilateral sensorimotor cortex injury in the rat

Although treatment with N-methyl-D-aspartate (NMDA) receptor antagonists reduce neuronal loss after cerebral infarction and brain trauma in laboratory animals, there is little data concerning the effects of these drugs on behavioral recovery. Because NMDA receptor antagonists impede certain kinds of learning, and because motor recovery after sensorimotor cortex injury in the rat is dependent on post-lesion experience, we hypothesized that treatment with MK-801 after focal brain injury would be detrimental. Groups of rats were first trained to traverse a narrow elevated beam and then subjected a right sensorimotor cortex suction-ablation lesion. In the first experiment, 24 h later, each rat received a single dose of either saline or the NMDA receptor antagonist MK-801 (0.5, 1.0, or 2.0 mg/kg). Beam-walking recovery was measured over the next 12 days. In a second experiment, rats were given 3 doses of MK-801 (0.5 mg/kg) at 24 h intervals beginning 24 h after cortex injury. In a third experiment, lesioned and sham-operated rats were allowed to recover for 12 days and then given MK-801 (0.5 mg/kg). Despite obvious behavioral effects of the drug, there was no overall difference in beam-walking performances among the treatment groups in any of the experiments. If 're-learning' is involved in motor recovery after cortex injury, the present results suggest that the process is not susceptible to permanent disruption by the early or late administration of an NMDA receptor antagonist.     

MK 801, an OBS N-methyl-D-aspartate channel blocker, does not improve the functional recovery nor spinal cord blood flow after spinal cord compression in rats

Damage to the central nervous system is followed by local release of excitatory amino acids, e.g. glutamate. These have been claimed to increase the metabolic need of already hypoxic neurons, and thereby to promote cell death. To investigate whether N-methyl-D-aspartate (NMDA) receptor-mediated mechanisms are involved in the damage consequent to spinal cord injury, 20 rats were exposed to 5-min compression of the thoracic spinal cord produced with a load of 35 g on a 2.2 x 5 mm sized plate. One group of animals was given a noncompetitive NMDA channel blocker, MK-801, in a dose of 10 mg/kg b.w and one group saline alone. The neurologic function was evaluated on the inclined plane for 4 days when spinal cord blood flow (SCBF) was measured with the 14C-iodoantipyrine autoradiographic technique. One day after trauma the animals in both groups were paraparetic and exhibited a significantly decreased capacity angle at the inclined plane test (about 35 degrees compared with about 63 degrees before compression). Thereafter, the motor function improved slightly, but to a similar extent in the two groups. On Day 4, gray and white matter SCBF was similar in the two groups. The results indicate that MK 801 in the dose used does not prevent the development of neurologic dysfunction or the reduction in SCBF after spinal cord compression.     

FK506 increases peripheral nerve regeneration after chronic axotomy but not after chronic schwann cell denervation

Poor functional recovery after peripheral nerve injury is attributable, at least in part, to chronic motoneuron axotomy and chronic Schwann cell (SC) denervation. While FK506 has been shown to accelerate the rate of nerve regeneration following a sciatic nerve crush or immediate nerve repair, for clinical application, it is important to determine whether the drug is effective after chronic nerve injuries. Two models were employed in the same adult rats using cross-sutures: chronic axotomy and chronic denervation of SCs. For chronic axotomy, a chronically (2 months) injured proximal tibial (TIB) was sutured to a freshly cut common peroneal (CP) nerve. For chronic denervation, a chronically (2 months) injured distal CP nerve was sutured to a freshly cut TIB nerve. Rats were given subcutaneous injections of FK506 or saline (5 mg/kg/day) for 3 weeks. In the chronic axotomy model, FK506 doubled the number of regenerated motoneurons identified by retrograde labeling (from 205 to 414 TIB motoneurons) and increased the numbers of myelinated axons (from 57 to 93 per 1000 microm2) and their myelin sheath thicknesses (from 0.42 to 0.78 microm) in the distal nerve stump. In contrast, after chronic denervation, FK506 did not improve the reduced capacity of SCs to support axonal regeneration. Taken together, the results suggest that FK506 acts directly on the neuron (as opposed to the denervated distal nerve stump) to accelerate and promote axonal regeneration of neurons whose regenerative capacity is significantly reduced by chronic axotomy.