Exercise in type 2 diabetes: genetic, metabolic and

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BJSM Online First, published on May 13, 2017 as 10.1136/bjsports-2016-096724

Review

Exercise in type 2 diabetes: genetic, metabolic and neuromuscular adaptations. A review of the evidence Silvano Zanuso,1 Massimo Sacchetti,2 Carl Johan Sundberg,3,4 Giorgio Orlando,2 Paolo Benvenuti,5 Stefano Balducci6 1

Centre for Applied Biological & Exercise Science, Coventry University Faculty of Health and Life Sciences, Coventry, UK 2 Human Movement and Sport Science, University of Rome, Rome, Italy 3 Department of Physiology & Pharmacology, Karolinska Institutet, Stockholm, Sweden 4 Department of Learning, Informatics, Management and Ethics, Karolinska Institutet, Stockholm, Sweden 5 Departmentof Neurological and Movement Sciences, Universityof Verona, Verona, Italy 6 Metabolic Fitness Association, Monterotondo (Rome), Italy Correspondence to Dr. Silvano Zanuso, Via Martiri d’Ungheria, 65 47521 Cesena (FC) Italy ; ​szanuso@​technogym.​com Accepted 13 March 2017

Abstract The biological responses to exercise training are complex, as almost all organs and systems are involved in interactions that result in a plethora of adaptations at the genetic, metabolic and neuromuscular levels. To provide the general practitioner and the sports medicine professionals with a basic understanding of the genetic, metabolic and neuromuscular adaptations at a cellular level that occur with aerobic and resistance exercise in subjects with type 2 diabetes. For each of the three domains (genetic, metabolic and neuromuscular), the results of the major systematic reviews and original research published in relevant journals, indexed in PubMed, were selected. Owing to limitations of space, we focused primarily on the role of skeletal muscle, given its pivotal role in mediating adaptations at all levels. Generally, training-induced adaptations in skeletal muscle are seen as changes in contractile proteins, mitochondrial function, metabolic regulation, intracellular signalling, transcriptional responses and neuromuscular modifications. The main adaptation with clinical relevance would include an improved oxidative capacity derived from aerobic training, in addition to neuromuscular remodelling derived from resistance training. Both training modalities improve insulin sensitivity and reduce cardiovascular risk. Taken together, the modifications that occur at the genetic, metabolic and neuromuscular levels, work correlatively to optimise substrate delivery, mitochondrial respiratory capacity and contractile function during exercise.

Introduction

To cite: Zanuso S, Sacchetti M, Sundberg CJ, et al. Br J Sports Med Published Online First: [please include Day Month Year]. doi:10.1136/ bjsports-2016-096724

Over the past decade, a large number of randomised controlled trials, meta-analyses and reviews have supported the benefits of physical activity and exercise for the prevention of type 2 diabetes mellitus (T2DM), providing clear and strong evidence.1 2 In addition, exercise and not solely that of physical activity, results in a variety of physiological and metabolic adaptations depending on the modality and type of exercise. Aerobic and resistance exercise represent the two extremes of an ideal continuum of training modalities and their benefits are summarised and presented in the latest American College of Sports Medicine/American Diabetes Association (ACSM/ADA) position statement.3 These recommendations are based on a large body of experimental evidence drawn mainly from three large long-term randomised controlled trials (RCTs). The first two are the Diabetes Aerobic and Resistance Exercise (DARE) study4 and the Health

benefits of Aerobic and Resistance Training in individuals with type 2 Diabetes (HART-D) study.5 These demonstrated that combined aerobic and resistance training is more effective than either one alone in reducing glycated haemoglobin (HbA1c) in patients with T2DM. However, in the DARE study4 it was unclear whether the additional benefit observed for the combination-exercise group (aerobic + resistance training) was due to the combination of training or to the extra exercise time. This question was dealt with by the HART-D study,5in which the interventions were designed to have approximately equal time and caloric expenditure for each type of tra ining modality (aerobic, resistance and their combination). A subsequent systematic review and meta-analysis including those two studies showed that structured exercise, either aerobic, resistance, or both, is associated with HbA1c reduction in patients with T2DM, especially if carried out for more than 150 min/week and when combined with dietary advice.6 The third RCT, the Italian Diabetes and Exercise Study (IDES), showed that a strategy combining a supervised mixed (aerobic and resistance) exercise training progrjrnlBibRefamme with structured exercise counselling was more effective than counselling alone in improving physical fitness and quality of life, ameliorating HbA1c and other modifiable cardiovascular risk factors, reducing coronary heart disease 10-year risk scores and reducing the number and/or dosage of medications, in a large cohort of sedentary subjects with T2DM.7 In a more recent study, the effects of aerobic and resistance training at a molecular or metabolic level8 or specifically on the molecular mechanism that led to adaptations in skeletal muscle in response to resistance training,9 have been the object of investigation to explain the modifications at the molecular and metabolic level. Neuromuscular deterioration in T2DM often leads to severe functional limitations,10 affecting both mass and fibre composition in skeletal muscle,11 12 leading to reduced muscle strength and power.13 14 Exercise then constitutes an effective strategy to stimulate adaptations that counteract neuromuscular dysfunction in T2DM,11 although the available literature has focused more on the effects of resistance training rather than aerobic training. If we consider the exercise benefits mentioned above at a genetic, metabolic and neuromuscular level, we find a growing body of literature now confirms the benefits of both aerobic and resistance training at these three levels in those with T2DM when performing aerobic + resistance

Zanuso S, et al. Br J Sports Med 2017;0:1–8. doi:10.1136/bjsports-2016-096724

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Review training. Generally, it is now commonly accepted that the effects of aerobic exercise are well established and interventions with more vigorous exercise programmes result in greater overall benefits. It appears that resistance training could be an effective intervention at all levels, even if the role of intensity, frequency and duration have not been sufficiently explored. Finally, combined-exercise training seems to be associated with additional significant improvements in overall metabolic control in comparison with aerobic or resistance training alone. However, the available evidence comes from studies that are often very specific, using differing modalities and hence difficult to compare using the strict criteria of systematic reviews. The purpose of this narrative review is to summarise the genetic, metabolic and neuromuscular adaptations to exercise that occur with aerobic and resistance training. The studies were selected by the authors through PubMed; MEDLINE, EMBASE, Scopus and Web of Science. Three of the authors identified all publications between 1990 and 2015 containing the keywords: T2DM, muscle adaptation, RCTs, systematic reviews. The publications were independently scanned by the authors to determine those that were considered relevant; the rest were discarded. Opinions expressed in this narrative review are also based on personal experience as authors, peer reviewers and editors. The primary focus is on adaptations in skeletal muscle, given its pivotal role in mediating the adaptations at all levels that may account for the variability in individual response, although there are still some aspects to be explored such as the role of intensity, frequency and duration of various types of exercise in T2DM. We will first consider phenotypic adaptation to different types of exercise with a reflection on individual responsiveness. We will then consider metabolic and neuromuscular adaptations. As we aim to provide information that can be applied in practice, a summary statement after each major section in the manuscript about the current evidence base is presented.

Exercise, genetics and epigenetics

Extended periods of regular exercise, both resistance and aerobic (eg, continuous or high-intensity interval training, lead to a continuum of distinctive phenotypic adaptations. High mechanical loads during resistance exercise cause increases in the strength of skeletal muscle through fibre hypertrophy, via protein synthesis,15 16 improved substrate use and aerobic capacity through angiogenesis,17 18 mitochondrial biogenesis19 and an increase in the number of the glucose transporter GLUT4.20 Such changes facilitate glucose uptake in skeletal muscle, which improves glucose control. The mechanisms that underlie the adaptations are induced by complex cellular signalling events, including protein modifications and changes in gene activity. A major factor behind the magnitude of the training response is the dose—that is, the intensity, duration and frequency of exercise. The stimuli affecting skeletal muscle cells can be divided into two major categories, intracellular and extracellular. Intracellular stimuli include mechanical tension, cytoplasmic calcium concentrations, oxygen tension, pH, temperature, adenosine monophosphate/ adenosine triphosphate (AMP/ATP) ratio and reactive oxygen species (ROS). Whereas extracellular stimuli result from α motor neuron activation through release of acetylcholine and, possibly, trophic factors, release of growth factors and cytokines, immune cell activity, hormones, blood-borne substrates and variations in blood flow and shear stress. Repeated bouts of exercise significantly affect the activity (number of copies of mRNA) of thousands of protein-coding 2

genes.21 22 The increase of mitochondrial protein content appears to result from the cumulative effects of transient bursts in their corresponding mRNAs after each exercise bout.23 Even minor levels of physical activity, such as interrupted sitting, can lower blood glucose and insulin levels and induce expression of metabolically relevant genes in skeletal muscle of overweight/obese non-diabetic subjects.24 In addition, a single bout of high-intensity interval training with as little as 4×30 s of exercise is enough to markedly elevate a key mitochondrial regulator, the transcriptional coactivator PGC-1α.25 Even though these studies were not specifically conducted in subjects with T2DM, their findings are significant considering that physical inactivity is a major cause of T2DM.

AMP-activated kinase (AMPK) activity and AS160 phosphorylation

A 40 min aerobic exercise bout at 70% of VO2max in obese subjects with T2DM showed an attenuated exercise-stimulated AMPK activity and AS160 phosphorylation, but normal exercise-induced increases in PGC-1 and nuclear respiratory factor 1 (NRF-1) expression.26 This could indicate a somewhat lower responsiveness to acute exercise and the authors speculated whether obese patients with T2DM need to exercise at a higher intensity to achieve similar effects as lean subjects. However, it has also been shown that six sessions of low-volume, high-intensity interval training (10×1 min cycling bouts at −90% maximal heart rate with 1 min rest in between) over 2 weeks can significantly improve glucose regulation as well as skeletal muscle mitochondrial content and GLUT-4 transporter abundance in patients with T2DM.27

DNA adaptations

It was previously thought that almost 99% of the genome that does not encode proteins28 lacked any specific function— thus called ‘junk DNA’. However, over the past decade it has become clear that most of the so called ‘non-coding’ majority of the genome can be transcribed and has biological functions.28 One example is microRNAs (miRNAs), small RNA strands that inhibit translation, which have been shown to be regulated by exercise training.29 miRNAs may play a role in skeletal muscle of T2DM, since an association between downregulation of several miRNAs and potential targeting of insulin signalling has been demonstrated.30 Acute aerobic exercise in humans has also been shown to induce changes in skeletal muscle DNA methylation at a few promoter sites.31 Lindholm et al22 found that 3 months of aerobic training induces human skeletal muscle DNA methylation changes at almost 4000 specific sites across the genome, which were associated with functionally relevant transcriptional changes, many of which occurred in regulatory enhancer regions. The differentially methylated sites were associated with transcription factor binding sites for myogenic regulatory factors and the ETS family. Of particular interest in the present context, are individuals with a family history of T2DM who have a different DNA methylation pattern at baseline from those without the disease.32 Also, a 6-month exercise intervention changes DNA methylation in the skeletal muscle of patients with T2DM.33

Individual responsiveness

It has been known for over 30 years that there is large interindividual variability in responsiveness to exercise,34 35 with a continuum of responses, some individuals responding strongly ('high-responders’) and others to a very limited extent Zanuso S, et al. Br J Sports Med 2017;0:1–8. doi:10.1136/bjsports-2016-096724

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Review ('low-responders’).36 Studies have shown that high-responders seem to activate key genes to a greater extent than low-responders.21 37 Genetic variability seems to explain around half of the heritability for training responsiveness,34 and some studies have put forward sets of gene variants that may explain part of that variability.36–39 However, from an analysis of 1687 people from five separate studies, it may be concluded that only a small fraction of people seem to respond poorly after regular exercise training, as shown by several or all disease risk factors that were measured (blood pressure, high-density lipoprotein cholesterol, triglycerides, insulin and cardiorespiratory fitness).40 It has also been shown that endurance training in people with T2DM is associated with significant improvements in metabolic parameters, irrespective of improvement in cardiorespiratory fitness.41 New evidence demonstrates that DNA hypomethylation is linked to the exercise response in skeletal muscle33 and that baseline expression may influence responsiveness both in healthy individuals21 and in patients with T2DM.42 Individuals for whom a a certain type of training has insufficient effect when conducted over a longer period of time, or who are not adherent to the exercise programme, should be helped by their clinician to modify their approach to possibly obtain better results. It could entail an increase in weekly dose by either increasing total exercise time or using some of the sessions for higher-intensity exercise. Alternatively, a change to another type of exercise might be useful. On making those modifications strategies of behavioural change could be used.

Summary statement

The available evidence for any difference in adaptation due to age or sex is limited. To date, most studies that have compared the magnitude or characteristics of the effects of exercise in different groups have found no major differences. As an example, Lindholm et al22 showed that 3 months of endurance training had very similar effects on both muscular performance improvement and changes in gene expression. The adaptation to different types of exercise, aerobic versus resistance training, is highly specific with an initial increase in mitochondrial volume fraction and capillary density, and the latter also increasing muscle mass and strength. There is also a clear relation between dose (intensity, duration and frequency) and the magnitude of the improvements.

Exercise modalities and metabolic adaptations

Exercise has a fundamental role in improving overall metabolic health and in reducing cardiovascular risk factors in subjects with T2DM.7 Those effects are the result of an interplay between various body systems, where skeletal muscle plays a pivotal role in the regulation of the metabolic homoeostasis8 and in mediating many of the benefits of exercise. At rest, skeletal muscle, under insulin-stimulated conditions is the predominant site of glucose disposal.43 Being the largest glycogen storage organ it represents a significant percentage of total body mass in both men and women44 and it accounts for 30% of the basal metabolic rate.45 Both aerobic and resistance exercise modalities determine a number of positive metabolic adaptations resulting from contractile and ion pumping bioenergetics that regulate molecular processes governing skeletal muscle adaptation that, in turn, contributes to the metabolic control in subjects with T2DM. A number of meta-analyses and reviews have highlighted the benefits of both aerobic46 47 and resistance training9 and their combination.48 49 Aerobic exercise interventions were generally Zanuso S, et al. Br J Sports Med 2017;0:1–8. doi:10.1136/bjsports-2016-096724

found to have a clinically significant effect on VO2max, with higher intensity exercise providing additional benefits on cardiorespiratory fitness and metabolic control.46 Resistance exercise was generally found to improve insulin sensitivity and glucose tolerance, while improving lean body mass and strength parameters.9 The three randomised controlled studies4 5 7 of long duration and statistically powerful owing to the number of participants, have demonstrated that combined training seems to have better effects on the major indicator of good metabolic control, HbA1c, than aerobic or resistance training alone. Thus, both aerobic and resistance exercise promote significant health benefits in subjects with T2DM but the basic mechanisms underlying the benefits deriving from aerobic and resistance exercise are distinct and they have different effects on the overall metabolic health of the patients. Aerobic exercise activates a number of mechanisms determined by an increase in muscular contraction that stimulates AMP and AMPK, the mitogen-activated protein kinase (MAPK), the release of calcium from endoplasmic reticulum and the Ca2+ calmodulin-dependent protein kinase II (CAMKII). In short-term aerobic exercise, those signalling mechanisms stimulate the translocation of GLUT-4 onto the cell membrane, facilitating the mechanism of non-insulin-dependent glucose uptake.50 When those mechanism are elicited repeatedly over time as the result of an exercise programme, mitochondrial biogenesis and angiogenesis increase. Muscular contraction activates the PGC1α (peroxisome-proliferator activated receptor-gamma coactivator 1α), that determines an increased ATP synthesis through the stimulation of NRF-1 and NRF-2. The effects of resistance training on glucose metabolism, mitochondrial function and biogenesis51 52 may be modulated by variants in genes such as PPARG or NDUFB6.53 An increased content of mitochondria within the cell muscle in turn facilitates improved fatty acid oxidation, with positive effects on metabolic control. The modifications induced by resistance training improve the activation of the insulin signalling cascade with better metabolic control,54 and an increase in muscle strength and muscle mass via muscle hypertrophy and neuromuscular remodelling.9 However, better metabolic control can occur even independently of a significant muscle increase,55 indicating that the benefits of resistance training are not solely dependent on skeletal muscle mass but also on intrinsic alterations within the muscle. One of the main pathways responsible for muscle growth is the activation of the insulin-like growth factor-1 pathway (or IGF-1/P13K/AKT). IGF-1 plays a fundamental role in muscle growth and regeneration through several intracellular signalling pathways. It activates AKT (a protein kinase) that stimulates protein synthesis via mammalian target of rapamycin (mTOR).56 Another important metabolic effect induced by resistance training is in glycaemic control determined by the stimulation of glycogen synthesis mediated by AKT via inhibition of the glycogen synthase kinase GSK3,57 and a robust increase in muscle glycogen content.58 Improving glycogen synthesis has positive metabolic effects because skeletal muscle insulin resistance in subjects with type T2DM is associated with lower muscle glycogen concentration, possibly owing to impaired glucose transport and glycogen synthesis.59 The activation of AMPK, one of the principal mechanisms facilitating the non-insulin-dependent glucose uptake60 is also increased with resistance exercise and not only with aerobic activity. It has been proposed that AMPK action may prevent muscle protein synthesis during exercise, but afterwards, inhibition (of mTOR) is released and protein synthesis is facilitated.61 The activation of AMPK occurring with resistance training, 3

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Review similarly to aerobic training, results in an increased translocation of GLUT-4 onto the cellular membrane and an increase of fatty acid oxidation.62 In addition to improved muscle mass, glycogen synthesis and non-insulin-dependent glucose uptake, resistance training induces a shift in the muscle fibre type distribution from low-oxidative type 2x muscle fibres to moderate-oxidative, more insulin sensitive type 2a muscle fibres.63

Summary statement

Both aerobic and resistance exercises and their combination promote significant health benefits in subjects with T2DM. Aerobic exercise interventions have a clinically significant effect on VO2max, with higher-intensity exercise providing additional benefits on cardiorespiratory fitness and metabolic control. Resistance exercise improves insulin sensitivity and glucose tolerance, while improving lean body mass and strength parameters. Both forms of exercise and their combination can assist with management of blood glucose levels, lipids, blood pressure, cardiovascular risk, mortality and quality of life. In order to be effective, exercise must be undertaken regularly and most people with T2DM can exercise safely.

Neuromuscular dysfunction in type 2 diabetes

It is widely accepted that T2DM is associated with a deterioration of neuromuscular function and performance, which may lead to severe functional limitations and loss of independence.10 63 64 Such defects occur from the initial stage of the disease and are aggravated by the onset of diabetic complications.13 64 Diabetic peripheral neuropathy (DPN) has a determinant role because it is responsible for a denervation combined with an insufficient re-innervation,65 leading to progressive loss of motor axons,66 an alteration of motor unit properties67 and structural changes in muscle fibre.64 These detrimental effects of diabetes are linked with a reduction in muscle strength, power and quality (torque per unit of muscle), in both the upper and lower body muscle areas.13 14 68–74 However, diabetic neuromuscular dysfunction affects the legs more than the arms,14 69 72 with major detrimental effects on the knee extensor,14 72 and the ankle plantar-flexor and dorsiflexor muscles.69 73 Differences in insulin sensitivity and mitochondrial function among muscular areas and the selective effects of diabetic neuropathy on peripheral motor nerve function have been suggested as possible causes for this regional effect of diabetes.66 75 76 Recent data suggest that patients with T2DM may be more susceptible to premature muscle fatigue, supporting the hypothesis that defective muscle endurance is another typical component of diabetic neuromuscular dysfunction.77 78 This higher muscle fatigability has been reported in patients with or without DPN, but the question of whether or not this is dependent on, or aggravated by, motor nerve damage has not been directly answered. In addition, T2DM may affect both mass and fibre composition in skeletal muscle.11 Evidence demonstrates a reduction in appendicular muscle mass, especially at the knee,79 80 with an additional effect of DPN, which is linked to marked muscle atrophy occurring at an earlier stage in the muscle structure of the foot and progressing to the lower leg.81 In parallel with impaired muscle mass in T2DM, several cross-sectional studies have reported an alteration in muscle fibre composition.12 82 However, the evidence on this remains unclear because some authors reported both a greater proportion of type II muscle fibres and a lower proportion of type I muscle fibres,12 82 whereas others found no significant differences between healthy and diabetic subjects.75 80 The reasons for this discrepancy are 4

unclear but may be related to differences in medication usage, the duration of the disease, the degree of glycaemic control and the level of physical activity reported. It is well recognised that resistance training is an effective strategy for counteracting neuromuscular dysfunction in T2DM.11 Numerous clinical and experimental studies have shown that supervised resistance exercise programmes lead to an increase in muscle strength, power, quality, endurance and muscle mass.83–87 As an example, 16 weeks of high-intensity progressive resistance training resulted in a 33% improvement in muscle strength and in a significant increase in lean muscle mass in patients with T2DM.83 Similarly, a training programme centred on muscle hypertrophy effectively procured a relevant increase in muscle mass and enhanced upper and lower body muscle strength after 4 months.84 Whereas, resistance training, characterised by moderate intensity, has been shown to enhance strength and also muscle endurance, highlighting a potentially time-effective strategy.86 87 In addition, low- to moderate-intensity resistance training has been reported to be a safe and effective strategy to counteract the detrimental effect of DPN on neuromuscular function. This is due to significant improvements in muscle strength with a low risk of adverse events.88–90 At the myocellular level, the few studies investigating morphological adaptations to resistance exercise in T2DM observed no changes in muscle fibre composition;91 however, an increase in cross-sectional area of both type I and type II muscle fibres has been documented.92 93 This increase appears to be lower in patients with T2DM than in healthy subjects, promoting the hypothesis that the adaptability of muscle fibres to resistance training may be altered by the diabetic state.94 However, the paucity of data on these points, does not allow us to reach a firm conclusion. Besides the changes in muscle fibre size, it would appear that an increase in muscle quality can be achieved with resistance training,92 although the effect on muscle fibre specific tension is still to be explored in relation to diabetes. Much needs to be explored about the effects of the parameters characterising resistance training on neuromuscular function in T2DM. For example, an attempt to gather data on exercise intensity showed there is a clear lack of consensus on how this parameter could/should be modulated to counteract the diabetic neuromuscular dysfunction. A promising strategy may be to focus on the adoption of high-speed movement (power training), as the strength deficit with T2DM has been shown to be higher at faster angular velocities.14 Indeed, power training has been shown to be a successful and safe option for elderly patients, as it specifically counteracts the degeneration of neuromuscular function with age and improves the ability to perform activities of daily living.95 Unfortunately, data on the effect of power training on muscle function in patients with T2DM are scarce, although the results of Ibáñez et al,96 who found an increase in muscle mass, strength and power of both the upper and lower limb muscles, are encouraging. It is also worth mentioning that power training was proved to be effective in ameliorating both glucose control and body composition in older patients with T2DM.97 98 In addition to resistance exercise, aerobic training may also have a positive effect on muscle involvement in diabetic neuromuscular dysfunction. Unfortunately, this topic has been poorly investigated, although an increase of leg muscle strength in patients with T2DM after a period of aerobic training (treadmill or cycling) has been documented.84 99 The genetic and molecular mechanisms (see figure 1) determine a number of basic neuromuscular and metabolic chronic modifications (see figure 2) that have a significant impact in clinical practice due to improved metabolic control and a reduction in cardiovascular risk. Zanuso S, et al. Br J Sports Med 2017;0:1–8. doi:10.1136/bjsports-2016-096724

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Review

Figure 1  Genetic and molecular mechanisms involved in acute and chronic aerobic and resistance training adaptations.

Summary statement

T2DM is associated with multiple neuromuscular defects, which include reduced muscle strength, power, mass and quality and a higher fatigability. Such deficits are more pronounced within the lower body muscle structure and are exacerbated by the presence of DPN. Resistance exercise is an effective tool for the prevention and treatment of diabetic neuromuscular dysfunction. In the absence of diabetic complications, patients with T2DM should perform moderate- to high-intensity resistance exercise, involving the major muscle groups and with specific focus on the lower limbs. In light of a more pronounced strength deficit at the higher contraction velocities, resistance training centred

on muscle power may be considered. Patients with DPN should perform low- to moderate-intensity resistance exercise, especially involving the distal and proximal segment of the lower limbs. Although combined endurance and resistance training is the first choice for metabolic control, its effect on neuromuscular function (including a possible interference) of patients with T2DM remains to be fully clarified.

Conclusions

Exercise training determines a number of acute and chronic adaptations that occur at the chromosomal, metabolic and

Figure 2  Basic neuromuscular and metabolic chronic modifications induced by aerobic and resistance training ↔, parameter remain unchanged; ↑, small increase; ↑↑, moderate increase; ↑↑↑, large increase; ↓, small decrease; ↓↓, moderate decrease; ↓↓↓, large decrease; Ø, insufficient evidence available. DPN, diabetic peripheral neuropathy. Zanuso S, et al. Br J Sports Med 2017;0:1–8. doi:10.1136/bjsports-2016-096724

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Review neuromuscular level, with skeletal muscle playing a pivotal role in mediating those modifications. Extended periods of regular exercise lead to a continuum of distinctive phenotypic adaptations that range from improved muscle strength to an improved substrate use and aerobic capacity through angiogenesis, mitochondrial biogenesis and an increased glucose transporter. The stimuli affecting skeletal muscle cells can be divided into two types: intracellular (such as mechanical tension, cytoplasmic calcium concentrations, oxygen tension, pH, temperature, AMP/ATP ratio and ROS) and extracellular (including α motor neuron activation, release of growth factors and cytokines, immune cell activity, hormones, bloodborne substrates and variations in blood flow and shear stress). Over the past decade, increased attention has been paid to the epigenetic regulation of exercise-induced gene expression changes, where the main epigenetic mechanisms are DNA methylation and histone protein modifications. From a genetic standpoint, the differences between high-responders and low-responders is interesting but to a large extent unsolved. Genetics seems to explain close to half of the variability in training responsiveness but some evidence shows that for a very small fraction of people all disease risk factors respond poorly following regular exercise training.40 From a metabolic point of view both aerobic and resistance exercise lead to a number of positive metabolic adaptations. Aerobic exercise improves reductions in HbA1c and increase in VO2max and in insulin sensitivity. Resistance exercise is generally found to improve insulin sensitivity and glucose tolerance, while improving lean body mass and strength parameters. Studies of whether combined resistance and aerobic training offer a synergistic and incremental effect on glycaemic control, have demonstrated that combined training has better effects on the major indicator of good metabolic control, HbA1c, than the effects of aerobic or resistance training alone.5 The basic mechanisms underlying the metabolic modifications that stimulate the non-insulin-dependent glucose uptake are AMP and AMPK, the mitogen-activated protein kinase (MAPK), the release of calcium from endoplasmic reticulum and the Ca2+ calmodulin-dependent protein kinase II (CAMKII). Other mechanisms, directly or indirectly related to improved metabolic control and elicited primarily by resistance training, include activation of PGC-1α that determines an increased ATP synthesis through the stimulation of NRF-1 and NRF-2 and activation of the IGF-1 pathway that stimulates protein synthesis. At the neuromuscular level it is well recognised that resistance training is an effective strategy to counteract neuromuscular dysfunction in T2DM, where DPN has a predominant role, leading to progressive loss of motor axons, an alteration of motor unit properties and structural changes in muscle fibre. These detrimental effects of diabetes are linked to reduced muscle strength and power and a possible concomitant alteration in muscle fibre composition. Resistance training has been shown to improve muscle mass and strength effectively and safely. At the myocellular level, increases in cross-sectional area of type I and type II muscle fibres have been reported and also improvement of muscle quality (torque per unit of muscle). Power training has also been shown to be a successful and safe option for elderly patients, as this specifically counteracts the degeneration of neuromuscular function with age and improves the ability to perform activities of daily living. Aerobic training may also have a positive effect on diabetic neuromuscular dysfunction, but this subject has been poorly investigated. In conclusion, exercise can be seen as a powerful 6

tool in the prevention and treatment of T2DM, with a number of positive modifications that occur at a genetic, metabolic and neuromuscular level.

What are the new findings? ►► The positive effects of aerobic training and resistance

training are well established. Aerobic exercise interventions have a clinically significant effect on VO2max, with higher intensity exercise providing additional benefits on cardiorespiratory fitness and metabolic control. Resistance exercise improves insulin sensitivity and glucose tolerance, while improving lean body mass and strength parameters. Both forms of exercise and their combination can assist with management of blood glucose levels, lipids, blood pressure, cardiovascular risk, mortality and quality of life. ►► Training-induced adaptations in skeletal muscles are seen as changes in contractile protein, mitochondrial function, metabolic regulation, intracellular signalling, transcriptional responses and neuromuscular modifications. ►► The modifications that occur at genetic, metabolic and neuromuscular levels work together to optimise substrate delivery, mitochondrial respiratory capacity and contractile function during exercise. ►► For neuromuscular dysfunction, the effects and benefits of resistance training have been better investigated than those of aerobic training. How might it impact on clinical practice in the near future? ►► It provides a basic and easy understanding of the main

long-term neuromuscular and metbolic chronic modifications induced by aerobic and resistance training adaptations. Specifically, it highlights how both aerobic and resistance training cause gene expression changes and proteome changes (eg, mitochondrial regulators and contractile protein regulators for aerobic and resistance training, respectively). It shows how many repeated exercise bouts over a longer period cause a number of chronic adaptations: mitochondrial biogenesis, improved glucose transport and angiogenesis due to aerobic training; increased contractile protein (X-sectional area) and improved glucose transport due to resistance training. ►► It provides a basic and easy understanding of the main long-term neuromuscular and metabolic chronic modifications induced by aerobic and resistance training. The main neuromuscular modifications related to the muscle are strength, power, endurance, quality, fibre size and composition, conduction velocity and motor sensory function and symptoms of diabetic peripheral neuropathy. The main long-term metabolic adaptations are resting insulin level, insulin sensitivity, cardiovascular risk reduction, body fat and lean body mass, aerobic capacity, oxidative capacity and anaerobic capacity. Acknowledgements  There are no additional contributors to be acknowledged for this submission. Contributors  CJS reviewed the literature and wrote the part related to 'Exercise,genetic and epigenetics'; SB and PB reviewed the literature and wrote the part related to 'Exercise modalities and metabolic modifications'; MS and GO reviewed the literature and wrote the part related to 'Neuromuscular dysfunction in type 2 diabetes'. SZ coordinated the overall process and wrote the manuscript. Zanuso S, et al. Br J Sports Med 2017;0:1–8. doi:10.1136/bjsports-2016-096724

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Review Competing interests  None declared. Provenance and peer review  Not commissioned; externally peer reviewed. © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

References

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Exercise in type 2 diabetes: genetic, metabolic and neuromuscular adaptations. A review of the evidence Silvano Zanuso, Massimo Sacchetti, Carl Johan Sundberg, Giorgio Orlando, Paolo Benvenuti and Stefano Balducci Br J Sports Med published online May 13, 2017

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