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This study aimed to unfold the implicit interplay of open innovation (OI) and perceived insider status (PIS) between the relationship of proactive personality (PP) and innovative work behavior (IWB). The phenomenon studied the moderated mediation of OI and PIS through the combined optic of the theory of innovation and the broaden-and-build theory. The nature of this study was post-positivist. The two-step approach of structural equation modeling was implemented. First, quantitative data were collected through an online questionnaire from the employees of IT industries in China. The study sample consisted of 460 responses used for data analysis in SPSS and AMOS version 26. This study was based on mediated moderation, which was statistically similar to Model 15 of the process macro. There were six hypotheses based on the theoretical framework. The result of H6 was rejected, which demonstrated that the conditional direct effect of OI and PIS mediated moderation on PP and IWB. The results comprehensively testified to the theoretical framework.

Human genetic disorders and transgenic mouse models have shown that mitochondrial DNA (mtDNA) mutations and telomere dysfunction instigate the aging process. Epidemiologically, exercise is associated with greater life expectancy and reduced risk of chronic diseases. While the beneficial effects of exercise are well established, the molecular mechanisms instigating these observations remain unclear. Endurance exercise reduces mtDNA mutation burden, alleviates multisystem pathology, and increases lifespan of the mutator mice, with proofreading deficient mitochondrial polymerase gamma (POLG1). We report evidence for a POLG1-independent mtDNA repair pathway mediated by exercise, a surprising notion as POLG1 is canonically considered to be the sole mtDNA repair enzyme. Here, we show that the tumor suppressor protein p53 translocates to mitochondria and facilitates mtDNA mutation repair and mitochondrial biogenesis in response to endurance exercise. Indeed, in mutator mice with muscle-specific deletion of p53, exercise failed to prevent mtDNA mutations, induce mitochondrial biogenesis, preserve mitochondrial morphology, reverse sarcopenia, or mitigate premature mortality. Our data establish a new role for p53 in exercise-mediated maintenance of the mtDNA genome and present mitochondrially targeted p53 as a novel therapeutic modality for diseases of mitochondrial etiology.

Obesity is a progressive chronic disease that is defined by increased adiposity and dysregulated blood lipid and glucose profiles. This, coupled with insulin resistance and hypertension, leads to the development of the metabolic syndrome in obese patients. Furthermore, obesity correlates strongly with an elevated risk and progression of a number of different cancers. Endurance exercise is a gold standard method for rescuing obesity and the associated metabolic dysfunction. Physical activity stimulates fat loss, evokes metabolic adaptations and induces browning of white adipose tissue. The ‘brown’ fat depots are thermogenically active, thereby facilitating energy expenditure and weight loss. New evidence suggests that the systemic effects of exercise are mediated by extracellular vesicles (EVs). These are released from all cell types, and contain canonical myokines that are shed from skeletal muscle, as well as a plethora of other molecular cargo including miRNA, mRNA, DNA, metabolites and proteins. Pro-metabolic myokines include proteins, as well as miRNAs that are linked to rescuing obesity and associated metabolic syndrome. Circulating miRNAs have been shown to be useful biomarkers of pathological conditions including obesity, cancer and the metabolic syndrome. EVs and their enclosed molecular cargo offers a viable therapeutic target for future studies designed to mimic exercise and recapitulate the beneficial effects of exercise in obese subjects.

Background: Exercise promotes numerous phenotypic adaptations in skeletal muscle that contribute to improved function and metabolic capacity. An emerging body of evidence suggests that skeletal muscle also releases a myriad of factors during exercise, termed “myokines”. The purpose of this study was to examine the effects of high-intensity interval training (HIIT) on the acute regulation of the mRNA expression of several myokines, including the prototypical myokine interleukin-6 (IL-6), and recently identified myokines fibronectin type III domain-containing protein 5 (FNDC5) (irisin) and meteorin-like protein (METRNL). Methods: Both before and after a 20-day period of twice-daily high-volume HIIT, 9 healthy males (20.5 ± 1.5 years performed a standardized bout of high-intensity interval exercise (HIIE; 5 × 4 min at ~80% pretraining peak power output) with skeletal muscle biopsy samples (vastus lateralis) obtained at rest, immediately following exercise, and at 3 h recovery. Results: Before training, a single bout of HIIE increased IL-6 (p

New Findings What is the central question of this study? Are there sex-based differences in the acute skeletal muscle response to sprint interval training (SIT)? What is the main finding and its importance? In response to a SIT protocol that involved three 20 s bouts of ‘all-out’ cycling, the expression of multiple genes associated with mitochondrial biogenesis, metabolic control and structural remodelling was largely similar between men and women matched for fitness. Our findings cannot explain previous reports of sex-based differences in the adaptive response to SIT and suggest that the mechanistic basis for these differences remains to be elucidated. A few studies have reported sex-based differences in response to several weeks of sprint interval training (SIT). These findings may relate to sex-specific responses to an acute session of SIT. We tested the hypothesis that the acute skeletal muscle response to SIT differs between sexes. Sedentary but healthy men (n = 10) and women (n = 9) were matched for age (22 ± 3 versus 22 ± 3 years old) and cardiorespiratory fitness [45 ± 7 versus 43 ± 10 ml O2 (kg fat-free mass)−1 min−1], with women tested in the mid-follicular phase of their menstrual cycles. Subjects performed three 20 s ‘all-out’ cycling efforts against a resistance of 5% of body mass, interspersed with 2 min of recovery. Relative mean power outputs [7.6 ± 0.5 versus 7.5 ± 0.9 W (kg fat-free mass)−1] were similar between men and women (P > 0.05). Furthermore, there were no differences in the exercise-induced changes in mRNA expression of PGC-1α, PRC, PPARD, SIRT1, RIP140, HSL, HKII, PDK4, PDP1, FOXO3, MURF-1, Myf5, MyoD and VEGFA at 3 h of recovery versus rest (P

Endurance exercise-mediated multisystemic adaptations are known to mitigate metabolism-related disorders such as obesity and type 2 diabetes mellitus (T2DM). However, the underlying molecular mechanisms that promote crosstalk between organs and orchestrate the pro-metabolic effects of endurance exercise remain unclear. Exercise-induced release of peptides and nucleic acids from skeletal muscle and other organs (collectively termed 'exerkines') has been implicated in mediating these systemic adaptations. Given that the extracellular milieu is probably not a hospitable environment for labile exerkines, a lipid vehicle-based mode of delivery has originated over the course of evolution. Two types of extracellular vesicles, exosomes and microvesicles, have been shown to contain proteins and nucleic acids that participate in a variety of physiological and pathological processes. Exosomes, in particular, have been shown to facilitate the exchange of peptides, microRNA, mRNA and mitochondrial DNA between cells and tissues. Intriguingly, circulatory extracellular vesicle content increases in an intensity-dependant manner in response to endurance exercise. We propose that the systemic benefits of exercise are modulated by exosomes and/or microvesicles functioning in an autocrine, paracrine and/or endocrine manner. Furthermore, we posit that native or modified exosomes, and/or microvesicles enriched with exerkines will have therapeutic utility in the treatment of obesity and T2DM.

Endurance exercise is known to induce metabolic adaptations in skeletal muscle via activation of the transcriptional co-activator peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α). PGC-1α regulates mitochondrial biogenesis via regulating transcription of nuclear-encoded mitochondrial genes. Recently, PGC-1α has been shown to reside in mitochondria; however, the physiological consequences of mitochondrial PGC-1α remain unknown. We sought to delineate if an acute bout of endurance exercise can mediate an increase in mitochondrial PGC-1α content where it may co-activate mitochondrial transcription factor A to promote mtDNA transcription. C57Bl/6J mice (n = 12/group; ♀ = ♂) were randomly assigned to sedentary (SED), forced-endurance (END) exercise (15 m/min for 90 min), or forced endurance +3 h of recovery (END+3h) group. The END group was sacrificed immediately after exercise, whereas the SED and END+3h groups were euthanized 3 h after acute exercise. Acute exercise coordinately increased the mRNA expression of nuclear and mitochondrial DNA-encoded mitochondrial transcripts. Nuclear and mitochondrial abundance of PGC-1α in END and END+3h groups was significantly higher versus SED mice. In mitochondria, PGC-1α is in a complex with mitochondrial transcription factor A at mtDNA D-loop, and this interaction was positively modulated by exercise, similar to the increased binding of PGC-1α at the NRF-1 promoter. We conclude that in response to acute altered energy demands, PGC-1α re-localizes into nuclear and mitochondrial compartments where it functions as a transcriptional co-activator for both nuclear and mitochondrial DNA transcription factors. These results suggest that PGC-1α may dynamically facilitate nuclear-mitochondrial DNA cross-talk to promote net mitochondrial biogenesis.

Habitual endurance exercise training is associated with multisystemic metabolic adaptations that lower the risk of inactivity-associated disorders such as obesity and type 2 diabetes mellitus (T2DM). Identification of complex systemic signaling networks responsible for these benefits are of great interest because of their therapeutic potential in metabolic diseases; however, specific signals that modulate the multisystemic benefits of exercise in multiple tissues and organs are only recently being discovered. Accumulated evidence suggests that muscle and other tissues have an endocrine function and release peptides and nucleic acids into the circulation in response to acute endurance exercise to mediate the multisystemic adaptations. Factors released from skeletal muscle have been termed myokines and we propose that the total of all factors released in response to endurance exercise (including peptides, nucleic acids, and metabolites) be termed, "exerkines." We propose that many of the exerkines are released within extracellular vesicles called exosomes, which regulate peripheral organ cross talk. Exosomes (30-140 nm) and larger microvesicles [MVs] (100-1000 nm) are subcategories of extracellular vesicles that are released into the circulation. Exosomes contain peptides and several nucleic acids (microRNA [miRNA], messenger RNA [mRNA], mitochondrial DNA [mtDNA]) and are involved in intercellular/tissue exchange of their contents. An acute bout of endurance exercise increases circulating exosomes that are hypothesized to mediate organ cross talk to promote systemic adaptation to endurance exercise. Further support for the role of exosomes (and possibly MVs) in mediating the systemic benefits of exercise comes from the fact that the majority of the previously reported myokines/exerkines are found in extracellular vesicles databases (Vesiclepedia and ExoCarta). We propose that exosomes isolated from athletes following exercise or exosomes bioengineered to incorporate one or many of known exerkines will be therapeutically useful in the treatment of obesity, T2DM, and other aging-associated metabolic disorders.

Mitochondrial DNA (mtDNA) mutator mice express a mutated form of mtDNA polymerase gamma that results an accelerated accumulation of somatic mtDNA mutations in association with a premature aging phenotype. An exploratory metabolomic analysis of cortical metabolites in sedentary and exercised mtDNA mutator mice and wild-type littermate controls at 9–10 months of age was performed. Pathway analysis revealed deficits in the neurotransmitters acetylcholine, glutamate, and aspartate that were ameliorated by exercise. Nicotinamide adenine dinucleotide (NAD) depletion and evidence of increased poly(adenosine diphosphate–ribose) polymerase 1 (PARP1)activity were apparent in sedentary mtDNA mutator mouse cortex, along with deficits in carnitine metabolites and an upregulated antioxidant response that largely normalized with exercise. These data highlight specific pathways that are altered in the brain in association with an accelerated age-related accumulation of somatic mtDNA mutations. These results may have relevance to age-related neurodegenerative diseases associated with mitochondrial dysfunction, such as Alzheimer's disease and Parkinson's disease and provide insights into potential mechanisms of beneficial effects of exercise on brain function.

Mitochondrial dysfunction may contribute to age-associated muscle atrophy. Previous data has shown that resistance exercise (RE) increases mitochondrial gene expression and enzyme activity in older adults; however, the acute response to RE has not been well characterized. To characterize the acute mitochondrial response to unaccustomed RE, healthy young (21 ± 3 yr) and older (70 ± 4 yr) men performed a unilateral RE bout for the knee extensors. Muscle biopsies were taken at rest and 3, 24, and 48 h following leg press and knee extension exercise. The expression of the mitochondrial transcriptional regulator proliferator-activated receptor γ coactivator 1-α (PGC-1α) mRNA was increased at 3 h postexercise; however, all other mitochondrial variables decreased over the postexercise period, irrespective of age. ND1, ND4, and citrate synthase (CS) mRNA were all lower at 48 h postexercise, along with specific protein subunits of complex II, III, IV, and ATP synthase. Mitochondrial DNA (mtDNA) copy number decreased by 48 h postexercise, and mtDNA deletions were higher in the older adults and remained unaffected by acute exercise. Elevated mitophagy could not explain the reduction in mitochondrial proteins and DNA, because there was no increase in ubiquitinated voltage-dependent anion channel (VDAC) or its association with PTEN-induced putative kinase 1 (Pink1) or Parkin, and elevated p62 content indicated an impairment or reduction in autophagocytic flux. In conclusion, age did not influence the response of specific mitochondrial transcripts, proteins, and DNA to a bout of RE.

Recent research has suggested that transmembrane protein 65 (TMEM65) is localized within the inner mitochondrial membrane. Little else is known about its function. In this study we investigated the location and function of TMEM65. Further, we report the functional consequences of a novel homozygous splice variant (c.472+1G>A) in the TMEM65 gene in a patient with mitochondrial encephalomyopathy. Here we investigated the location of TMEM65 by immunofluorescence staining of the protein and by immunoblotting of the isolated mitochondrial fractions in healthy fibroblasts and those from the patient. To study the function of TMEM65 we knocked down mRNA using TMEM65-specific siRNA, and measured mitochondrial function by enzymology, protein abundance and oxygen consumption rate in fibroblasts. Subcellular fractionation confirmed that the TMEM65 protein was present in the inner mitochondrial membrane. Knocking down TMEM65 expression in dermal fibroblasts severely affected mitochondrial content and respiration rate. Further evidence for the essential role of TMEM65 in mitochondrial function came from the demonstration of severe cellular and clinical consequences resulting from the novel TMEM65 gene mutation. In conclusion, these findings suggest that TMEM65, an inner mitochondrial membrane protein, plays a significant role in mitochondrial respiratory chain function. We also provide the first evidence that a mutation in the TMEM65 gene results in mitochondrial dysfunction and a severe mitochondrial encephalomyopathy phenotype.

Somatic mtDNA mutations and deletions in particular are known to clonally expand within cells, eventually reaching detrimental intracellular concentrations. The possibility that clonal expansion is a slow process taking a lifetime had prompted an idea that founder mutations of mutant clones that cause mitochondrial dysfunction in the aged tissue might have originated early in life. If, conversely, expansion was fast, founder mutations should predominantly originate later in life. This distinction is important: indeed, from which mutations should we protect ourselves – those of early development/childhood or those happening at old age? Recently, high-resolution data describing the distribution of mtDNA deletions have been obtained using a novel, highly efficient method (Taylor et al., 2014). These data have been interpreted as supporting predominantly early origin of founder mutations. Re-analysis of the data implies that the data actually better fit mostly late origin of founders, although more research is clearly needed to resolve the controversy.

SummaryEndothelial dysfunction is a central hallmark of diabetes. The transcriptional coactivator PGC-1α is a powerful regulator of metabolism, but its role in endothelial cells remains poorly understood. We show here that endothelial PGC-1α expression is high in diabetic rodents and humans and that PGC-1α powerfully blocks endothelial migration in cell culture and vasculogenesis in vivo. Mechanistically, PGC-1α induces Notch signaling, blunts activation of Rac/Akt/eNOS signaling, and renders endothelial cells unresponsive to established angiogenic factors. Transgenic overexpression of PGC-1α in the endothelium mimics multiple diabetic phenotypes, including aberrant re-endothelialization after carotid injury, blunted wound healing, and reduced blood flow recovery after hindlimb ischemia. Conversely, deletion of endothelial PGC-1α rescues the blunted wound healing and recovery from hindlimb ischemia seen in type 1 and type 2 diabetes. Endothelial PGC-1α thus potently inhibits endothelial function and angiogenesis, and induction of endothelial PGC-1α contributes to multiple aspects of vascular dysfunction in diabetes.

The gut microbiota is the collective microbial community colonized within the lumen of the intestinal tract of the host. A growing body of evidence has demonstrated that the microbiome is capable of responding to environmental, dietary, pathological and genetic factors. Particularly of interest is novel research into the response of the gut microbiota to exercise stimulus as a potential therapeutic mechanism for exercise on metabolic diseases. Although experimental studies investigating the mechanisms governing the exercise-induced changes in the microbiota have been limited, preliminary data from animal and human studies implicate the microbiota in a wide range of host metabolic pathways that are modulated by exercise. This review outlines some of these findings and frames the microbiota within the context of energy metabolism, exercise and disease.

What is the central question of this study? Are there sex-based differences in the acute skeletal muscle response to sprint interval training (SIT)? What is the main finding and its importance? In response to a SIT protocol that involved three 20 s bouts of 'all-out' cycling, the expression of multiple genes associated with mitochondrial biogenesis, metabolic control and structural remodelling was largely similar between men and women matched for fitness. Our findings cannot explain previous reports of sex-based differences in the adaptive response to SIT and suggest that the mechanistic basis for these differences remains to be elucidated. A few studies have reported sex-based differences in response to several weeks of sprint interval training (SIT). These findings may relate to sex-specific responses to an acute session of SIT. We tested the hypothesis that the acute skeletal muscle response to SIT differs between sexes. Sedentary but healthy men (n = 10) and women (n = 9) were matched for age (22 ± 3 versus 22 ± 3 years old) and cardiorespiratory fitness [45 ± 7 versus 43 ± 10 ml O

The mtDNA mutator mouse lacks the proofreading capacity of the sole mtDNA polymerase, leading to accumulation of somatic mtDNA mutations, and a profound premature aging phenotype including elevated oxidative stress and apoptosis, and reduced mitochondrial function. We have previously reported that endurance exercise alleviates the aging phenotype in the mutator mice, reduces oxidative stress, and enhances mitochondrial biogenesis. Here we summarize our findings, with the emphasis on the central role of p53 in these adaptations. We demonstrate that mtDNA in sedentary and exercised PolG mice carry similar amounts of mutations in muscle, but in addition to that sedentary mice have more non-mutational damage, which is mitigated by exercise. It follows therefore that the profound alleviation of the mtDNA mutator phenotype in muscle by exercise may not require a reduction in mtDNA mutational load, but rather a decrease of mtDNA damage and/or oxidative stress. We further hypothesize that the observed 'alleviation without a reduction of mutational load' implies that the oxidative stress in PolG muscle is maintained, at least in part, by the 'malicious cycle', a hypothetical positive feedback potentially driven by the 'transcriptional mutagenesis', that is the conversion of chemically modified nucleotides into mutant RNA bases by the mitochondrial RNA polymerase.

Endurance exercise confers complete phenotype protection, suppresses early mortality, mitigates mitochondrial ROS-mediated oxidative damage, increases cellular antioxidant capacity, and 4 prevents cellular senescencmutator mice. Figure S2. Endurance exercise prevents dysregulated mitochondrial-induced apoptosis and reduces nuclear p53-mediated repression of PGC-1Îą and promotes mitochondrial biogenesis in mutator mice. Figure S3. Endurance exercise promotes systemic mitochondrial biogenesis in mtDNA mutator mice. Figure S4. Magnitude of mitochondrial ROS (physiological vs. pathological) regulates p53 subcellular localization. Figure S5. Pre-treatment with exogenous antioxidant preferentially shuttles p53 to mitochondria in response to stress. Figure S6. Endurance exercise-mediated attenuation of sarcopenia, increase in endurance capacity, skeletal muscle mitochondrial biogenesis, and repair of muscle mtDNA mutations is p53 dependent. Table S1. WT, PolG-SED, and PolG-END Skeletal Muscle Microarray IPA-GO Analysis. Table S2. Real-time PCR primer sequences. (PDF 1601Â kb)

Background Human genetic disorders and transgenic mouse models have shown that mitochondrial DNA (mtDNA) mutations and telomere dysfunction instigate the aging process. Epidemiologically, exercise is associated with greater life expectancy and reduced risk of chronic diseases. While the beneficial effects of exercise are well established, the molecular mechanisms instigating these observations remain unclear. Results Endurance exercise reduces mtDNA mutation burden, alleviates multisystem pathology, and increases lifespan of the mutator mice, with proofreading deficient mitochondrial polymerase gamma (POLG1). We report evidence for a POLG1-independent mtDNA repair pathway mediated by exercise, a surprising notion as POLG1 is canonically considered to be the sole mtDNA repair enzyme. Here, we show that the tumor suppressor protein p53 translocates to mitochondria and facilitates mtDNA mutation repair and mitochondrial biogenesis in response to endurance exercise. Indeed, in mutator mice with muscle-specific deletion of p53, exercise failed to prevent mtDNA mutations, induce mitochondrial biogenesis, preserve mitochondrial morphology, reverse sarcopenia, or mitigate premature mortality. Conclusions Our data establish a new role for p53 in exercise-mediated maintenance of the mtDNA genome and present mitochondrially targeted p53 as a novel therapeutic modality for diseases of mitochondrial etiology.

Low-volume, high-intensity interval training (HIT) increases skeletal muscle mitochondrial capacity, yet little is known regarding potential mechanisms promoting this adaptive response. Our purpose was to examine molecular processes involved in mitochondrial biogenesis in human skeletal muscle in response to an acute bout of HIT. Eight healthy men performed 4 × 30-s bursts of all-out maximal intensity cycling interspersed with 4 min of rest. Muscle biopsy samples (vastus lateralis) were obtained immediately before and after exercise, and after 3 and 24 h of recovery. At rest, the majority of peroxisome proliferator-activated receptor γ coactivator (PGC)-1α, a master regulator of mitochondrial biogenesis, was detected in cytosolic fractions. Exercise activated p38 MAPK and AMPK in the cytosol. Nuclear PGC-1α protein increased 3 h into recovery from exercise, a time point that coincided with increased mRNA expression of mitochondrial genes. This was followed by an increase in mitochondrial protein content and enzyme activity after 24 h of recovery. These findings support the hypothesis that an acute bout of low-volume HIT activates mitochondrial biogenesis through a mechanism involving increased nuclear abundance of PGC-1α.

A causal role for mitochondrial DNA (mtDNA) mutagenesis in mammalian aging is supported by recent studies demonstrating that the mtDNA mutator mouse, harboring a defect in the proofreading-exonuclease activity of mitochondrial polymerase gamma, exhibits accelerated aging phenotypes characteristic of human aging, systemic mitochondrial dysfunction, multisystem pathology, and reduced lifespan. Epidemiologic studies in humans have demonstrated that endurance training reduces the risk of chronic diseases and extends life expectancy. Whether endurance exercise can attenuate the cumulative systemic decline observed in aging remains elusive. Here we show that 5 mo of endurance exercise induced systemic mitochondrial biogenesis, prevented mtDNA depletion and mutations, increased mitochondrial oxidative capacity and respiratory chain assembly, restored mitochondrial morphology, and blunted pathological levels of apoptosis in multiple tissues of mtDNA mutator mice. These adaptations conferred complete phenotypic protection, reduced multisystem pathology, and prevented premature mortality in these mice. The systemic mitochondrial rejuvenation through endurance exercise promises to be an effective therapeutic approach to mitigating mitochondrial dysfunction in aging and related comorbidities.

High-intensity interval training (HIT) induces skeletal muscle metabolic and performance adaptations that resemble traditional endurance training despite a low total exercise volume. Most HIT studies have employed ‘all out’, variable-load exercise interventions (e.g. repeated Wingate tests) that may not be safe, practical and/or well tolerated by certain individuals. Our purpose was to determine the performance, metabolic and molecular adaptations to a more practical model of low-volume HIT. Seven men (21 ± 0.4 years, ml kg−1 min−1) performed six training sessions over 2 weeks. Each session consisted of 8–12 × 60 s intervals at ∼100% of peak power output elicited during a ramp peak test (355 ± 10 W) separated by 75 s of recovery. Training increased exercise capacity, as assessed by significant improvements on both 50 kJ and 750 kJ cycling time trials (P < 0.05 for both). Skeletal muscle (vastus lateralis) biopsy samples obtained before and after training revealed increased maximal activity of citrate synthase (CS) and cytochrome c oxidase (COX) as well as total protein content of CS, COX subunits II and IV, and the mitochondrial transcription factor A (Tfam) (P < 0.05 for all). Nuclear abundance of peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) was ∼25% higher after training (P < 0.05), but total PGC-1α protein content remained unchanged. Total SIRT1 content, a proposed activator of PGC-1α and mitochondrial biogenesis, was increased by ∼56% following training (P < 0.05). Training also increased resting muscle glycogen and total GLUT4 protein content (both P < 0.05). This study demonstrates that a practical model of low volume HIT is a potent stimulus for increasing skeletal muscle mitochondrial capacity and improving exercise performance. The results also suggest that increases in SIRT1, nuclear PGC-1α, and Tfam may be involved in coordinating mitochondrial adaptations in response to HIT in human skeletal muscle.

Human aging is associated with a significant reduction in muscle mass (sarcopenia) resulting in muscle weakness and functional limitations in the elderly. Sarcopenia has been associated with mitochondrial dysfunction and the accumulation of mtDNA deletions. Resistance training increases muscle strength and size and can increase mitochondrial capacity and decrease oxidative stress in older adults. Creatine monohydrate (CrM) and conjugated linoleic acid (CLA) have biological effects that could enhance some of the beneficial effects of resistance training in older adults (i.e., ↑ fat-free mass, ↓ total body fat). We have completed two resistance-training studies with CrM alone and CrM + CLA supplementation in older adults to evaluate the independent effects of exercise and dietary supplements, as well as their interactive effects. Our studies, and several others, have found that CrM enhanced the resistance exercise mediated gains in fat-free mass and strength. More recently, we found that the addition of CLA also lead to a significant reduction of body fat after six months of resistance training in older adults. Older adults have fewer wild-type mtDNA copies and higher amounts of mtDNA deletions as compared with younger adults in mature skeletal muscle; however, these deletions are not seen in the satellite cell-derived myoblast cultures. These findings, and the fact that mtDNA deletions are lower and wild-type mtDNA copy number is higher after resistance training in older adults, suggests that activation of satellite cells secondary to resistance exercise-induced muscle damage can dilute or “shift” the proportion of mtDNA genotype towards that of a younger adult. Recent evidence suggests that CrM supplementation in combination with strength training can enhance satellite cell activation and total myonuclei number per muscle fiber in young men. Future studies are required to determine whether the mitochondrial adaptations to resistance exercise in older adults are further enhanced with CrM supplementation and whether this is due to increased recruitment of satellite cells. It will also be important to determine whether these changes are maintained over a longer time period.

Accumulating evidence from epidemiological and experimental studies indicate that obesity, and its related metabolic consequences of insulin resistance and type 2 diabetes, are associated with accelerated cognitive decline (Yates et al., 2012). The etiology of neurodegeneration in obesity is undoubtedly complex, with vascular, metabolic, inflammatory, and structural changes all likely to play a role (Yates et al., 2012). The discovery of leptin in 1994 and the subsequent advancement in our understanding that adipose tissue is an endocrine organ that can communicate with the brain to regulate appetite (Zhang et al., 1994) brings about the intriguing possibility that adipose-brain crosstalk can regulate aspects of neuronal physiology and pathology (Aguilar-Valles et al., 2015). Indeed neurons have been shown to express receptors for various adipokines, indicating that factors released from adipose tissue have the potential to communicate directly with the brain. Research in this area is relatively new, and while epidemiological data points towards the negative consequences of adipose-brain crosstalk (Whitmer et al., 2005), some intriguing new studies highlight that the secretory profile of adipose tissue might be involved in reduction in neurodegeneration via maintenance of neuronal viability (Tezapsidis et al., 2009; Wan et al., 2015).

Physical inactivity is a primary modifiable risk factor for obesity and type 2 diabetes (T2D) – metabolic diseases that are rampant in pediatric and adult population. Endurance exercise has been sh...

Brief, intense exercise training may induce metabolic and performance adaptations comparable to traditional endurance training. However, no study has directly compared these diverse training strategies in a standardized manner. We therefore examined changes in exercise capacity and molecular and cellular adaptations in skeletal muscle after low volume sprint-interval training (SIT) and high volume endurance training (ET). Sixteen active men (21 +/- 1 years, ) were assigned to a SIT or ET group (n = 8 each) and performed six training sessions over 14 days. Each session consisted of either four to six repeats of 30 s 'all out' cycling at approximately 250% with 4 min recovery (SIT) or 90-120 min continuous cycling at approximately 65% (ET). Training time commitment over 2 weeks was approximately 2.5 h for SIT and approximately 10.5 h for ET, and total training volume was approximately 90% lower for SIT versus ET ( approximately 630 versus approximately 6500 kJ). Training decreased the time required to complete 50 and 750 kJ cycling time trials, with no difference between groups (main effects, P

Several studies have illustrated that the polymerase gamma mutator (PolG) mice have reduced mitochondrial content secondary to systemic mitochondrial dysfunction, and subsequently a lower capacity to perform aerobic respiration and endurance exercise. We sought to delineate the extent of glycolysis as a means of energy production in the PolG mice in the absence of optimal mitochondrial function. PolG mice display an enhanced reliance on glycolysis as compared to their wild-type counterparts. This is evident by the resting hypoglycemia, higher PFK content, and elevated plasma lactate levels in the PolG mice. In vitro experiments provide further proof that PolG derived dermal fibroblasts have a higher rate of, and capacity for, glycolysis. PolG mice also have enhanced capacity to perform hepatic gluconeogenesis that is likely enhancing the Cori cycle capacity.

> Give every individual the right amount of exercise, not too little and not too much.1 > > —Hippocrates Physical activity has long been tied to good health. Hippocrates was guided by his theory of balanced humors to advocate that absolutely everyone, young or old, needs exercise, but not too much. A landmark 1953 study noted that drivers of public trolleys in London had twice as many acute coronary syndromes as did conductors of the same trolleys, the only notable difference being that conductors walked as they collected tickets and drivers sat.2,3 In the decades since this seminal epidemiological observation, nearly every aspect of human physiology has been demonstrated to benefit from exercise, ranging from lung and cardiac function to cognition and aging (Figure 1). The same decades, however, have witnessed a dramatic sedentarization of the US population (despite the newfound popularity of recreational exercise). Today, the consequences of sedentary lifestyles, synergizing with dramatic increases in caloric intake, are ubiquitous and devastating. Figure 1. The many long-term benefits of regular endurance exercise. Exercise is a fundamental component of the human condition. Humans are the only primates capable of sustained long-distance running, and this behavior likely significantly shaped the evolutionary departure of humans from other primates.4 For example, the need for heat dissipation during prolonged physical activity likely favored loss of body hair and the proliferation of sweat glands, thereby considerably altering the human form.5,6 Endurance exercise thus not only is good for us but in fact is part of what defines us. Not surprisingly, the study of exercise, including its mechanics, physiology, and health benefits, has long garnered fascination. Over the last decade, new molecular techniques have ushered in a new era of exercise research, focused on understanding fundamental mechanisms. The wealth of new information is staggering. …

The transcriptional coactivator peroxisome proliferator-activator receptor γ coactivator (PGC)-1α is required for full hypoxic induction of vascular endothelial growth factor (VEGF) in skeletal muscle cells. Under normoxic conditions, PGC-1α also strongly induces mitochondrial biogenesis, but PGC-1α does not activate this program under hypoxic conditions. How this specificity is achieved is not known. We show here that hypoxia specifically induces alternatively spliced species encoding for truncated forms of PGC-1α: NT-PGC-1α and PGC-1α4. NT-PGC-1α strongly induces VEGF expression, whereas having little effect on mitochondrial genes. Conditioned medium from cells expressing NT-PGC-1α robustly induces endothelial migration and tube formation, hallmarks of angiogenesis. Transgenic expression of PGC-1α4 in skeletal muscle in mice induces angiogenesis in vivo. Finally, knockdown of these PGC-1α isoforms and hypoxia-inducible factor-1α (HIF-1α) abrogates the induction of VEGF in response to hypoxia. NT-PGC-1α and/or PGC-1α4 thus confer angiogenic specificity to the PGC-1α-mediated hypoxic response in skeletal muscle cells.

It has been known for more than 4 decades that exercise causes increases in skeletal muscle mitochondrial enzyme content and activity (i.e., mitochondrial biogenesis). Increasing evidence now suggests that exercise can induce mitochondrial biogenesis in a wide range of tissues not normally associated with the metabolic demands of exercise. Perturbations in mitochondrial content and (or) function have been linked to a wide variety of diseases, in multiple tissues, and exercise may serve as a potent approach by which to prevent and (or) treat these pathologies. In this context, the purpose of this review is to highlight the effects of exercise, and the underlying mechanisms therein, on the induction of mitochondrial biogenesis in skeletal muscle, adipose tissue, liver, brain, and kidney.

Artificial selection in rat has yielded high-capacity runners (HCR) and low-capacity runners (LCR) that differ in intrinsic (untrained) aerobic exercise ability and metabolic disease risk. To gain insight into how oxygen metabolism may have been affected by selection, we compared mitochondrial function, oxidative DNA damage (8-dihydroxy-guanosine; 8dOHG), and antioxidant enzyme activities in soleus muscle (Sol) and gastrocnemius muscle (Gas) of adult and aged LCR vs. HCR rats. In Sol of adult HCR rats, maximal ADP-stimulated respiration was 37% greater, whereas in Gas of adult HCR rats, there was a 23% greater complex IV-driven respiratory capacity and 54% greater leak as a fraction of electron transport capacity (suggesting looser mitochondrial coupling) vs. LCR rats. H2O2 emission per gram of muscle was 24–26% greater for both muscles in adult HCR rats vs. LCR, although H2O2 emission in Gas was 17% lower in HCR, after normalizing for citrate synthase activity (marker of mitochondrial content). Despite greater H2O2 emission, 8dOHG levels were 62–78% lower in HCR rats due to 62–96% higher superoxide dismutase activity in both muscles and 47% higher catalase activity in Sol muscle in adult HCR rats, with no evidence for higher 8 oxoguanine glycosylase (OGG1; DNA repair enzyme) protein expression. We conclude that genetic segregation for high running capacity has generated a molecular network of cellular adaptations, facilitating a superior response to oxidative stress.