Bjorn T. Tam

Autophagic Cellular Responses to Physical Exercise in Skeletal Muscle

Autophagy is an evolutionarily conserved biological process that functions to recycle protein aggregate and malfunctioned organelles. The activation of autophagy can be stimulated by a number of ways including infection, caloric restriction, and physical exercise. In addition to cellular metabolism and cell survival/death machinery, autophagy plays an important role in the maintenance of cellular homeostasis in skeletal muscle especially during physical exercise in which energy demand can be extremely high. By degrading macromolecules and subcellular organelles through the fusion of autophagosomes and lysosomes, useful materials such as amino acids can be released and re-used to sustain normal metabolism in cells. Autophagy is suggested to be involved in glucose and lipid metabolism and is proposed to be a critical physiological process in the regulation of intracellular metabolism. The effects of physical exercise on autophagy have been investigated. Although physical exercise has been demonstrated to be an autophagic inducer, cellular autophagic responses to exercise in skeletal muscle appear to be varied in different exercise protocols and disease models. It is also not known whether the exercise-induced beneficial health consequences involve the favorable modulation of cellular autophagy. Furthermore, the cellular mechanisms of exercise-induced autophagy still remain largely unclear. In this review article, we discuss the general principle of autophagy, cellular signaling of autophagy, autophagic responses to acute and chronic aerobic exercise, and the potential cross-talks among autophagy, mitochondrial biogenesis, and ubiquitination. This article aims to stimulate further studies in exercise and autophagy.

Autophagic adaptation is associated with exercise‐induced fibre‐type shifting in skeletal muscle

Acute exercise is known to activate autophagy in skeletal muscle. However, little is known about how basal autophagy in skeletal muscle adapts to chronic exercise. In the current study we aim to, firstly, examine whether long‐term habitual exercise alters the basal autophagic signalling in plantaris muscle and, secondly, examine the association between autophagy and fibre‐type shifting.

Resveratrol protects against doxorubicin-induced cardiotoxicity in aged hearts through the SIRT1-USP7 axis

Doxorubicin induced functional deteriorations and elevations of USP7‐related apoptotic/catabolic signalling in the senescent heart Resveratrol protects against doxorubicin‐induced alterations through the restoration of SIRT1 deacetylase activity

Immediate effects of 2 different whole-body vibration frequencies on muscle peak torque and stiffness

OBJECTIVE To examine the immediate effects of 2 vibration protocols with different vibration frequencies that yielded the same maximum acceleration (106.75ms(-2)) on muscle peak torque and stiffness of knee extensor and flexor. DESIGN Randomized crossover study with repeated measures. SETTING Laboratory setting. PARTICIPANTS Recreationally active male adults (N=10). INTERVENTION Participants performed 10 bouts of 60-second static half squats intermitted with a 60-second rest period between bouts on a platform with no vibration (control) and a vibration frequency of 26Hz or 40Hz. MAIN OUTCOME MEASURES Concentric and eccentric peak torques of knee extensor and flexor were examined within 5 minutes before and after vibration by isokinetic test. Youngs modulus as an index of tissue stiffness was determined at quadriceps and hamstring pre- and postvibration by using an ultrasound indentation method. RESULTS The 2-way repeated-measures analysis of variance indicated a significant interaction effect between vibration and vibration frequency for knee extensor concentric peak torque (P=.003). The vibration-induced changes of knee extensor concentric peak torque in vibration frequency of 26Hz (14.5Nm) and 40Hz (12.0Nm) were found to be significantly greater than that in controls (-29.4Nm) (P<.05). The change in eccentric peak torque of knee flexor after vibration tended to be greater in 26Hz of vibration frequency when compared with controls (26Hz of vibration frequency vs controls: 13.9±7.1 vs -11.4±5.3Nm, P=.08). No statistically significant differences were obtained in tissue stiffness in the quadriceps and hamstring with any of the conditions. CONCLUSIONS Our data suggest that whole-body vibration at a frequency of 26Hz and 40Hz preclude the decline in concentric peak torque of knee extensor observed after 10 bouts of 60 seconds of static half squats. A change in muscle mechanical stiffness property as induced by whole-body vibration is not supported by our data.

Unacylated ghrelin restores insulin and autophagic signaling in skeletal muscle of diabetic mice

Impairment of insulin signaling in skeletal muscle detrimentally affects insulin-stimulated disposal of glucose. Restoration of insulin signaling in skeletal muscle is important as muscle is one of the major sites for disposal of blood glucose. Recently, unacylated ghrelin (UnAG) has received attention in diabetic research due to its favorable actions on improving glucose tolerance, glycemic control, and insulin sensitivity. The investigation of UnAG has entered phase Ib clinical trial in type 2 diabetes and phase II clinical trial in hyperphagia in Prader-Willi syndrome. Nonetheless, the precise mechanisms responsible for the anti-diabetic actions of UnAG remain incompletely understood. In this study, we examined the effects of UnAG on restoring the impaired insulin signaling in skeletal muscle of db/db diabetic mice. Our results demonstrated that UnAG effectively restored the impaired insulin signaling in diabetic muscle. UnAG decreased insulin receptor substrate (IRS) phosphorylation, increased protein kinase B (Akt) phosphorylation, and, hence, suppressed mTOR signaling. Consequently, UnAG enhanced Glut4 localization and increased PDH activity in the diabetic skeletal muscle. Intriguingly, our data indicated that UnAG normalized the suppressed autophagic signaling in diabetic muscle. In conclusion, our findings illustrated that UnAG restored the impaired insulin and autophagic signaling in skeletal muscle of diabetic mice, which are valuable to understand the underlying mechanisms of the anti-diabetic action of UnAG at peripheral skeletal muscle level.

Acute Treatment of Resveratrol Alleviates Doxorubicin-Induced Myotoxicity in Aged Skeletal Muscle Through SIRT1-Dependent Mechanisms

Study of the exacerbating effects of chemotherapeutics, such as doxorubicin, on the impairment of insulin metabolic signaling in aged skeletal muscle is very limited. Here, we tested the hypothesis that activation of sirtuin 1 deacetylase activity by resveratrol would prevent the disruption of insulin signaling and augmentation of catabolic markers induced by doxorubicin in aged skeletal muscle. Two- and 10-month-old senescence-accelerated mice (prone 8) were randomized to receive saline, doxorubicin, doxorubicin and resveratrol, or a combination of doxorubicin, resveratrol, and sirtinol or EX527. Doxorubicin reduced the sirtuin 1 activity without affecting the phosphorylation levels of IRS1(Ser307), mTOR(Ser2481), Akt(Thr308/Ser473), membranous glucose transporter 4, protein abundance of PDK4, and enzymatic activity of pyruvate dehydrogenase in aged muscles. Intriguingly, resveratrol attenuated the doxorubicin-induced elevations of apoptotic and catabolic markers measured as Bax, caspase 3 activity, apoptotic DNA fragmentation, MuRF-1, ubiquitinated proteins, and proteasomal activity in aged muscles, whereas these beneficial effects were abolished on inhibition of sirtuin 1 by sirtinol or EX527. Markers of insulin signaling were not affected by doxorubicin or resveratrol in the senescent skeletal muscle. Nevertheless, the antiapoptotic and anticatabolic effects of resveratrol in aged skeletal muscle treated with doxorubicin were mediated in a sirtuin 1-dependent signaling manner.

Doxorubicin Induces Inflammatory Modulation and Metabolic Dysregulation in Diabetic Skeletal Muscle.

Anti-cancer agent doxorubicin (DOX) has been demonstrated to worsen insulin signaling, engender muscle atrophy, trigger pro-inflammation, and induce a shift to anaerobic glycolytic metabolism in skeletal muscle. The myotoxicity of DOX in diabetic skeletal muscle remains largely unclear. This study examined the effects of DOX on insulin signaling, muscle atrophy, pro-/anti-inflammatory microenvironment, and glycolysis metabolic regulation in skeletal muscle of db/db diabetic and db/+ non-diabetic mice. Non-diabetic db/+ mice and diabetic db/db mice were randomly assigned to the following groups: db/+CON, db/+DOX, db/dbCON, and db/dbDOX. Mice in db/+DOX and db/dbDOX groups were intraperitoneally injected with DOX at a dose of 15 mg per kg body weight whereas mice in db/+CON and db/dbCON groups were injected with the same volume of saline instead of DOX. Gastrocnemius was immediately harvested, weighed, washed with cold phosphate buffered saline, frozen in liquid nitrogen, and stored at −80°C for later analysis. The effects of DOX on diabetic muscle were neither seen in insulin signaling markers (Glut4, pIRS1Ser636∕639, and pAktSer473) nor muscle atrophy markers (muscle mass, MuRF1 and MAFbx). However, DOX exposure resulted in enhancement of pro-inflammatory favoring microenvironment (as indicated by TNF-α, HIFα and pNFκBp65) accompanied by diminution of anti-inflammatory favoring microenvironment (as indicated by IL15, PGC1α and pAMPKβ1Ser108). Metabolism of diabetic muscle was shifted to anaerobic glycolysis after DOX exposure as demonstrated by our analyses of PDK4, LDH and pACCSer79. Our results demonstrated that there might be a link between inflammatory modulation and the dysregulation of aerobic glycolytic metabolism in DOX-injured diabetic skeletal muscle. These findings help to understand the pathogenesis of DOX-induced myotoxicity in diabetic muscle.

Autophagic adaptations to long-term habitual exercise in cardiac muscle

Autophagy has been shown to be responsive to physical exercise. However, the effects of prolonged habitual exercise on autophagy in cardiac muscle remain unknown. The present study aimed to examine whether long-term habitual exercise alters the basal autophagic signalling in cardiac muscle. Female Sprague-Dawley rats aged 2 months were randomly assigned to control and exercise groups. Animals in exercise group were kept in cages with free access exercise wheels to perform habitual exercise for 5 months. Animals in the control group were placed in cages without exercise wheels. Ventricular muscle tissues were harvested for analysis after 5 months. Phosphorylation statuses of upstream autophagic regulatory proteins and protein expressions of downstream autophagic facts remained unchanged in the cardiac muscle of exercise animals when compared to control animals. Intriguingly, the protein abundance of microtubule-associated protein-1 light chain -3 II (LC3-II), heat shock protein 72 (HSP72) and peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) were significantly increased in cardiac muscle of exercise rats relative to control rats. 5 months of habitual exercise causes the adaptive increase in LC3-II reserve without altering autophagic flux, which probably contributes to the elevation of cellular autophagic capacity and efficiency of cardiac muscle.

Revealing the neural mechanisms underlying the beneficial effects of Tai Chi : a neuroimaging perspective

Tai Chi Chuan (TCC), a traditional Chinese martial art, is well-documented to result in beneficial consequences in physical and mental health. TCC is regarded as a mind-body exercise that is comprised of physical exercise and meditation. Favorable effects of TCC on body balance, gait, bone mineral density, metabolic parameters, anxiety, depression, cognitive function, and sleep have been previously reported. However, the underlying mechanisms explaining the effects of TCC remain largely unclear. Recently, advances in neuroimaging technology have offered new investigative opportunities to reveal the effects of TCC on anatomical morphologies and neurological activities in different regions of the brain. These neuroimaging findings have provided new clues for revealing the mechanisms behind the observed effects of TCC. In this review paper, we discussed the possible effects of TCC-induced modulation of brain morphology, functional homogeneity and connectivity, regional activity and macro-scale network activity on health. Moreover, we identified possible links between the alterations in brain and beneficial effects of TCC, such as improved motor functions, pain perception, metabolic profile, cognitive functions, mental health and sleep quality. This paper aimed to stimulate further mechanistic neuroimaging studies in TCC and its effects on brain morphology, functional homogeneity and connectivity, regional activity and macro-scale network activity, which ultimately lead to a better understanding of the mechanisms responsible for the beneficial effects of TCC on human health.

Protective Effect of Unacylated Ghrelin on Compression-Induced Skeletal Muscle Injury Mediated by SIRT1-Signaling

Unacylated ghrelin, the predominant form of circulating ghrelin, protects myotubes from cell death, which is a known attribute of pressure ulcers. In this study, we investigated whether unacylated ghrelin protects skeletal muscle from pressure-induced deep tissue injury by abolishing necroptosis and apoptosis signaling and whether these effects were mediated by SIRT1 pathway. Fifteen adult Sprague Dawley rats were assigned to receive saline or unacylated ghrelin with or without EX527 (a SIRT1 inhibitor). Animals underwent two 6-h compression cycles with 100 mmHg static pressure applied over the mid-tibialis region of the right limb whereas the left uncompressed limb served as the intra-animal control. Muscle tissues underneath the compression region, and at the similar region of the opposite uncompressed limb, were collected for analysis. Unacylated ghrelin attenuated the compression-induced muscle pathohistological alterations including rounding contour of myofibers, extensive nucleus accumulation in the interstitial space, and increased interstitial space. Unacylated ghrelin abolished the increase in necroptosis proteins including RIP1 and RIP3 and attenuated the elevation of apoptotic proteins including p53, Bax, and AIF in the compressed muscle. Furthermore, unacylated ghrelin opposed the compression-induced phosphorylation and acetylation of p65 subunit of NF-kB. The anti-apoptotic effect of unacylated ghrelin was shown by a decrease in apoptotic DNA fragmentation and terminal dUTP nick-end labeling index in the compressed muscle. The protective effects of unacylated ghrelin vanished when co-treated with EX527. Our findings demonstrated that unacylated ghrelin protected skeletal muscle from compression-induced injury. The myoprotective effects of unacylated ghrelin on pressure-induced tissue injury were associated with SIRT1 signaling.