doi:10.

1093/brain/awn264

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SCIENTIF IC COMMENTARY

T rain, train, train! No pain, just gain

Physical training in myopathy: yes or no? This highlights a long-standing dilemma, and one that is still a matter of debate and controversy. Is it beneficial, at least to avoid muscle deconditioning, or detrimental, even harmful, because of the mechanical stress imposed to wrecked myofibres? An initial consideration is that little attention has been given to the different responses to training that the various myopathic conditions can produce. A second, consequential one, is that lack of unequivocal results and flaws in the training protocols let physicians take a somewhat empirical attitudedictated by personal inclinations, common sense, indulgence toward patient compliance or just prudence inspired by primum non nocere - first do not harm, an old evergreen precept (Hippocrates, 460377 BC). In many cases, the final persuasion is that physical exercise is not recommended, through anxiety over the risk of damaging an already compromised muscle, or even triggering acute episodes of pain, rhabdomyolysis and myoglobinuria. The latter are certainly contraindications to strenuous physical exercise, for instance in several metabolic myopathies related to impaired energy metabolism, such as the lipid storage myopathies, due to defects of intra-mitochondrial transport and utilization of fatty acids (Bruno and DiMauro, 2008; e.g. carnitine-palmitoyl transferase II deficiency, electron transfer flavoprotein dehydrogenase (ETF-DH) deficiency, and very long-chain fatty acid b-oxidation defects) or glycogen (DiMauro, 2007; e.g. myophosphorylase deficiency and defects of intermediary glycolytic enzymes). Some defects of the mitochondrial respiratory chain are also associated with myoglobinuria, notably deficiency of CoQ10 (especially related to ETF-DH deficiency) and mutations in the MTCOB gene (Andreu et al., 1999), but in most cases neither high creatine kinase nor myoglobinuric episodes are frequent symptoms of mitochondrial disorders. In addition, little, if any, attention is paid to the quantitative and qualitative features of therapeutic physical training (van der Kooi et al., 2005). For instance, a fundamental difference exists between (aerobic) endurance and resistance training protocols. Aerobic exercise, or cardiorespiratory fitness training, consists of an activity, or combination of activities, using large muscle groups that can be maintained continuously and are rhythmical and aerobic in nature, e.g. walking-hiking, running-jogging, cycling, aerobic dance or swimming (American College of Sports Medicine, 1998). On the other hand, resistance training is carried out by making repeated muscle contractions against resistance and is performed primarily to improve muscle strength and mass (Kraemer, 2002). In turn, resistance training should be differentiated into eccentric versus concentric exercise. In eccentric exercise (e.g. downhill walking) the contracting muscle is forcibly lengthened; in concentric exercise it shortens (Proske and Morgan, 2001). While concentric contractions initiate movements, eccentric contractions slow or stop them. A unique feature of eccentric exercise is that untrained (normal) subjects become stiff and sore the following day because of structural damage to muscle fibres involving both the sarcolemma and the sarcomere. Therefore, for a given workload, eccentric resistance exercise is deemed to damage muscle fibres and induce muscle regeneration more than concentric exercise. For such studies to be feasible and adoptable, the design of both aerobic exercise interventions and strength (resistance) training programmes should be defined precisely and the protocols reported in detail. Information should be provided on the type(s) of exercise training, intensity (including progression rate), frequency, duration of each session and of the entire programme, trained muscle groups and supervision. The recommendations from the American College of Sports Medicine can be used as minimal requirements to come to an effective, standardized but safe and individualized exercise prescription taking into account the pre-training level of fitness. While patients with different neuromuscular disorders could participate in a single study, the data should be presented and analyzed individually for each specific muscle disease, as differences in their pathophysiology may determine reactions to training. Two papers in the current issue (Murphy et al., 2008; Sveen et al., 2008) deal with these important questions and provide new results in relation to two areas of human muscle disorders, namely the dystrophinopathies and the mitochondrial myopathies. Marie Louise Sveen and colleagues report on the results of a clinical trial based on exercise training in 11 adult patients affected by genetically and morphologically proven Becker muscular dystrophy (BMD). Since BMD is by definition a condition associated with structural damage of the myofibres as proven by severe morphological abnormalities and high serum creatine kinase values, restraint

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Scientific Commentary behind this seemingly paradoxical, if not villainous, intent? A very good one indeed that stems from an old, intriguing, and still unexplained observation that, whilst mature myofibres can carry high levels of mutant mtDNA including mtDNA, myoblasts usually do not. Myoblasts derive from precursor cells, also termed satellite cells, which are embedded between the sarcolemma and the basal membrane of myofibres. They are dormant cells in normal post-natal conditions, but can be reactivated and take part in muscle regeneration or hypertrophy under suitable stimuli. As a consequence, muscle regeneration in response to controlled damage or exercise-linked hypertrophy could induce the activation and recruitment of deletion-free satellite cells and determine a reduction of the mtDNA mutation load. Encouraging results were obtained along this line by two proof-of-principle experiments carried out in the late 1990s. Limited injury, induced by either myotoxic bupivucaine (Clark et al., 1997) or vigorous resistance exercise (Shoubridge, 1997), in muscles carrying deleterious mtDNA mutations of tRNA genes, was followed by reduction of mutation load and marked increase in the number of cytochrome c oxidase (COX) positive regenerating muscle fibers (COX is one of the respiratory chain complexes that are partly encoded by, and dependent on, intact mtDNA). Murphy et al. have now applied the same concept to investigate the potential therapeutic effects of prolonged (12 weeks) progressive overload leg resistance training in eight Chronic Progressive External Ophthalmoplegia patients with muscle-restricted, heteroplasmic mtDNAs. Results have again been encouraging: at the end of the training programme, all patients displayed increased muscle strength and improved muscle oxidative capacity, ostensibly due to myofibre regeneration and recruitment of satellite cells. However, these positive changes were associated with a limited fall of mtDNA mutation load (4.3%, not significant), suggesting that better performance may largely be due to the general effects of training rather than to a favourable genotype shift. It is possible that accumulation of mtDNA in ragged-red, severely abnormal areas along the muscle fibre can hamper or limit their clearance; it is also possible that the same triggers that induce activation of satellite cells may also stimulate mtDNA replication, which for shorter mtDNAs can be faster and more efficient than for normal-size mtDNA species. But there is another, more simple, possibilitynamely that the period of observation may have been just too short for the phenomena induced by resistance training to be completed, including mtDNA genotype shift. By and large, the results of this study are encouraging and promising; together with previous data from the same group (Taivassalo et al., 2001), they do suggest that controlled physical training is beneficial in certain types of mtDNA-associated muscle disorders, and warrant further investigation of this approach as a potential treatment. In conclusion, we can take a concordant message from these studies: controlled physical training protocols combine

from physical exercise and a sedentary lifestyle are often recommended in these patients. This view is supported by results of previous studies in both BMD patients and in a dystrophinopathy mouse model (the mdx mouse) consisting of training protocols involving eccentric resistance, or conducted at maximal exertion level. However, based on the above considerations, these interventions may predictably be unsuitable and indeed potentially deleterious in a dystrophic condition such as BMD. However, Sveen et al. used a submaximal endurance (aerobic) exercise programme based on 30 min cycloergometer sessions at 65% of maximal oxygen uptake (VO2max) to evaluate both safety and clinical improvement. The programme was carried out over 12 weeks, but interestingly six patients continued for a full year. The primary end-points of this study were VO2max, maximal workload (Wmax), plasma creatine kinase levels and self-reported questionnaires. Careful investigation of numerous output measures included needle muscle biopsies from the left vastus lateralis, taken before and after the 12-week programme, bi-monthly plasma creatine kinase determinations, dynamometer-based evaluation of muscle strength, daily living reports, total body DEXA scanning, and full vital capacity and echocardiography. Results were both sound and encouraging: no adverse reactions (e.g. no creatine kinase increment), and instead substantial increase of both VO2max and Wmax in patients versus controls, sustained increase in muscle strength, up to and possibly beyond 1 year, and self-reported improvements in endurance, leg muscle strength and walking distance. Importantly, no morphological changes were observed in the muscle biopsy taken at the end of the 12-week training period, suggesting that endurance exercise does not accelerate the exhaustion of the regenerative pool of muscle satellite cells. These results should prompt physicians to recommend low-tomoderate aerobic exercise in the management protocol of BMD, and warrant future investigation for other conditions associated with muscular dystrophy. In fact, results concordant with those by Sveen et al. were also reported by randomized controlled trials based on training protocols in myotonic dystrophy (Lindeman et al., 1995) or facioscapulo-humeral dystrophy (FSHD; van der Kooi et al., 2004) patients (reviewed by van der Kooi et al., 2005). Taken together, these studies support the idea that exercise programmes may indeed maximize muscle and cardiorespiratory function and prevent additional disuse atrophy in patients with specific muscle dystrophies, such as mild BMD, FSHD and myotonic dystrophy. The second paper, by Julie Murphy and colleagues, deals with a specific mitochondrial myopathysporadic, adultonset chronic progressive external ophthalmoplegia associated with a single, heteroplasmic deletion of mitochondrial DNA (mtDNA) in skeletal muscle. In this case a resistance, rather than endurance, training protocol was adopted, and Murphy et al. aimed in fact to damage the myofibres carrying abnormal mtDNA. What is the rationale

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Scientific Commentary clinical efficacy with other noteworthy features, such as low-cost, user-friendliness and high complianceat least in patients with sufficient residual motor capacityand exercise may itself trigger repair processes in affected muscles. Massimo Zeviani Unit of Molecular Neurogenetics Center for the Study of Childrens Mitochondrial Diseases Pierfranco and Luisa Mariani Foundation C. Besta Institute of Neurology IRCCS, Milan, Italy E-mail: zeviani@istituto-besta.it

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