 Concurrent training and CoQ10 in Multiple Sclerosis Eur J Transl Myol 33 (2) 11253, 2023 doi: 10.4081/ejtm.2023.11253 - 1 - Effects of concurrent training and CoQ10 on neurotrophic factors and physical function in people with Multiple Sclerosis: a pilot study Amir Hossein Haghighi (1), Amin Ahmadi (1), Antonio Carotenuto (2), Roya Askari (1), Karim Nikkhah (3), Behnam Bagherzadeh-Rahmani (1), Hadi Shahrabadi (1), Daniel Souza (4), Paulo Gentil (4,5) (1) Department of Exercise Physiology, Faculty of Sport Sciences, Hakim Sabzevari University, Sabzevar, Iran; (2) Department of Neurosciences, Reproductive and Odontostomatological Sciences, Federico II University, Naples, Italy; (3) Department of Neurology, Mashhad University of Medical Sciences, Mashhad, Iran; (4) College of Physical Education and Dance, Federal University of Goias, Goiania, Brazil; (5) Hypertension League, Federal University of Goias, Goiania, Brazil. This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (CC BY-NC 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. Abstract The present study aimed to investigate the effects of 8-week of coenzyme Q10 (CoQ10) supplementation alone or combined with concurrent training (CT) on functional capacity, serum brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF) in multiple sclerosis (MS) patients. Our hypothesis is that CT promotes improvements in the studied outcomes with higher results for the combination of CT and CoQ10. Randomized placebo-controlled trial. Twenty-eight patients with MS were randomly divided into 4 groups: CT+placebo, CT+CoQ10, CoQ10 and placebo. CT involved two resistance training sessions and one aerobic training session per week. CoQ10 was supplemented with 200 mg daily. Serum levels of BDNF, NGF and functional tests [timed up and go (TUG), 6-min walk (6MW), chest press, lateral pull down, leg extension, and lying leg curls one repetition maximum] were measured before and after the intervention period. CT+placebo and CT+CoQ10 significantly improved performance in TUG, 6MW, chest press, lateral pull down, leg extension, and lying leg curls, with superior results to both CoQ10 and placebo groups. Changes in TUG for CT+placebo were significantly higher than CT+CoQ10 (p<0.05). There were no significant differences in NGF and BDNF among the four groups (p >0.05). CT improves physical abilities in patient with MS, regardless CoQ10 supplementation. CT should be recommended for MS patients to increase functional capacity, but there seems to be no benefit in supplementing CoQ10. Key Words: Multiple sclerosis; neurodegenerative disease; exercise therapy; NGF; BDNF; resistance training; interval training; ubiquinone. Eur J Transl Myol 33 (2) 11253, 2023 doi: 10.4081/ejtm.2023.11253 Multiple sclerosis (MS) is the most common debilitating neurological disease among adults.1 MS is an autoimmune central nervous system disorder characterised by demyelination and neurodegeneration that leads to physical disability.2 Previous researches examined nutritional strategies that are potentially effective for MS management.3,4 Given the important role of inflammation, oxidative stress and mitochondrial dysfunction in MS development, treatments with anti- inflammatory and antioxidant supplements have received growing attention.5,6 Among them, coenzyme Q10 (CoQ10) is considered a promising therapeutic agent in neurodegenerative diseases. The administration of CoQ10 alone or in combination with other substances in mice with induced-neurodegenerative disease provided neuroprotective effects such as decreased brain oxidative stress and damage, as well as increased neurotrophic factors (e.g., BDNF).7,8 CoQ10 supplementation might be of potential interest due to its anti-inflammatory and antioxidant effects in MS patients,9 as well as its positive effects on fatigue and depressive symptoms.10 Physical exercise is also a potential therapeutic strategy for managing MS, and is considered safe and effective, with positive effects in fitness, functional capacity and quality of life.11 Exercise exerts its positive therapeutic effects through different pathways. It increases regeneration of sensory neurons after axonal injury, stimulates the Concurrent training and CoQ10 in Multiple Sclerosis Eur J Transl Myol 33 (2) 11253, 2023 doi: 10.4081/ejtm.2023.11253 - 2 - expression of genes associated with axon growth and regeneration, and improves nerve function.12,13 Physical exercise can also reduce MS symptoms by improving motor coordination, aerobic capacity and muscle strength.14 Moreover, physical exercise has been shown to increase the expression of neurotrophic factors such as brain derived neurotrophic factor (BDNF) and nerve growth factor (NGF).15,16 Although many different strategies have been used, the combination of resistance and aerobic training, known as concurrent training (CT), has been shown to be particularly beneficial for people with MS.17,18 Considering the potential benefits of CoQ10 supplementation in MS, it is plausible to suggest that it might exert additional effects when combined with CT. Therefore, the aim of the present study was to investigate the effects of eight weeks of a CT and CoQ10 supplementation on physical function, serum BDNF and NGF levels in people with MS. Our hypothesis is that CT would promote improvements in the studied outcomes with higher results for the combination of CT and CoQ10. Materials and Methods Participants The study involved 28 MS patients, among 3243 members of the Multiple Sclerosis Association of Mashhad (Iran). Inclusion criteria were: 1) MS diagnosis according to 2017 McDonald criteria;19 2) Expanded Disability Status Scale (EDSS) between 2 and 5; 3) No smoking history; 4) No history of regular exercise; 5) At least 2 years of stable disease modifying treatment; 6) Aged higher than 18 and lower or equal 4. We opted to select younger participants to avoid the confounding effects of age in the studied outcomes. Exclusion criteria: 1) MS relapse within 30 days from patient enrolment; 2) Moderate to severe cardiovascular disease (Stage III or IV, according to the New York Heart Association); 3) Any other condition that could be aggravated by the study protocol. This study was approved by relevant Ethics Committee and registered at Clinical Trials records (2019-08-11, 1398/05/20). All subjects or their parents provided a written informed consent prior to study participation. The study was performed in accordance with good clinical practices and Declarations of Helsinki. Study procedures Participants were divided into four groups: CT+placebo, CT+CoQ10, CoQ10, and placebo using a simple random method (lottery). Participants in the CoQ10 and placebo groups did not engage in any form of physical exercise during the study. CoQ10 was manufactured by Nutri Century (Canada) and ingested as one 200 mg capsule daily. Starch powder was used as placebo and its Fig 1. Study diagram Concurrent training and CoQ10 in Multiple Sclerosis Eur J Transl Myol 33 (2) 11253, 2023 doi: 10.4081/ejtm.2023.11253 - 3 - consumption was similar to the consumption of CoQ10 supplements. The study diagram is presented in Figure 1. Exercise protocol CT was performed three sessions per week (two resistance training sessions and one aerobic training session) for eight weeks. Every session started with a 5- 10 minutes warm-up and ended with 5-10 minutes cool down. Resistance training involved chest press, lateral pull down, leg extensions, and lying leg curls using a minimal dose approach. Exercises were performed in three sets of eight to 10 repetitions at 50-60% of one repetition maximum (1RM), 2-3 minutes rest between sets and 3-4 minutes between exercises. Aerobic exercises included moderate intensity interval training on a cycle ergometer. Training involved 5 to 12 bouts of 3 minutes interspersed by 1 minute of passive recovery. For exercise prescription, VO2peak was estimated through the Astrand bicycle aerobic test.20 Aerobic training started with 5 bouts at 50% of the peak oxygen consumption (VO2peak) in the first week and ended with 12 bouts at 60% VO2peak. Blood analysis Blood samples (5 cc) were collected 24 hours before the beginning of the study and 24 hours after the last training session, after 10 hours overnight fasting. Women were evaluated in the follicular stage (first 3 to 5 days of the cycle). BDNF (Human BDNF Elisa kit, Boster Biological Technology Co) and NGF concentration (Human NGF Elisa kit, Boster Biological Technology Co) were measured with ELISA method using specific kits. Functional tests Timed up and go (TUG) and 6-min walk (6MW) tests were used to evaluate physical functioning. Muscle strength was evaluated by estimated 1RM on chest press, lateral pull down, leg extension, and lying leg curls. Tests were performed in the beginning (24 hours before the first training session) and in the end of study period (48 hours after the last training session). All tests were performed using the same procedures and supervised by the same investigator, that was blind to group allocation. For TUG, participants stand up from a standard armchair, Table 1. Demographic and clinical features for enrolled subjects according to treatment group. CT + CoQ10 (n=7) CT + placebo (n=7) CoQ10 (n=7) Placebo (n=7) p-value Gender Men (%) Women (%) 4 (57.14) 3 (42.86) 4 (57.14) 3 (42.86) 4 (57.14) 3 (42.86) 4 (57.14) 3 (42.86) 1.000 Age, years median (Q1-Q3) 41.00 (40.00-45.00) 32.00 (28.00-45.00) 35.00 (32.00-44.00) 36.00 (31.00-44.00) 0.448 Weight, kg mean ± standard deviation 68.64 ± 3.70 66.50 ± 3.01 67.94 ± 2.21 68.50 ± 1.21 0.445 Height, cm mean ± standard deviation 167.00 ±3.83 162.14 ± 4.63 163.71 ± 5.68 165.43 ± 4.54 0.270 History of MS, years mean ± standard deviation 5.86 ± 1.35 4.86 ± 1.07 4.86 ± 2.03 4.86 ± 1.57 0.543 EDSS, score mean ± standard deviation 3.69 ± .052 3.79 ± 0.39 3.64 ± 0.75 3.64 ± 0.69 0.967 Vo2Peak (ml/kg/min) mean ± standard deviation 25.27±1.00 24.93±0.89 24.29±1.74 24.26±0.50 0.278 MS = Multiple sclerosis; EDSS = Expanded disability status scale Concurrent training and CoQ10 in Multiple Sclerosis Eur J Transl Myol 33 (2) 11253, 2023 doi: 10.4081/ejtm.2023.11253 - 4 - walked three meters as fast is possible, turned back, walked back to the chair, and sited down again. The test was performed twice, and the best result was used in the analysis. The 6MW test consisted in walking continuously as fast is possible around a 30 meters track for six minutes and the final distance achieved was recorded in meters. To calculate 1RM, participants performed each exercise to momentary muscle failure, Table 2. Outcome measures pre- and post- treatment. Groups Baseline Follow-up F p-value ES Daily calorie intake (kcal) mean± standard deviation CT + CoQ10 1977.90±181.97 2068.30±146.99 0.175 0.912 0.022 CT + placebo 2029.30±217.56 2009.00±242.11 CoQ10 2063.40±119.47 2056.90±189.65 Placebo 2080.30±151.63 1996.40±168.59 BDNF (ng/ml) mean± standard deviation CT + CoQ10 2.94±0.27 2.92±0.15 0.345 0.793 0.041 CT + placebo 2.81±0.42 2.81±0.47 CoQ10 2.89±0.13 3.04±0.16 Placebo 2.98±0.10 2.98±0.25 NGF (pg/ml) mean± standard deviation CT + CoQ10 376.14±41.38 399.00±54.02 0.267 0.849 0.034 CT + placebo 394.80±38.55 385.17±76.82 CoQ10 399.23±22.38 413.17±61.81 Placebo 428.23±105.56 407.46±34.79 Time up and go (s) mean±standard deviation CT + CoQ10 7.70±0.71 **6.79±0.51 23.262 ‡<0.001 0.752 CT + placebo 8.15±0.74 ***6.55±0.47 CoQ10 7.70±0.52 7.66±0.61 Placebo 7.61±0.71 7.72±0.92 6-min walk (m) mean±standard deviation CT + CoQ10 272.14±6.26 ***303.29±11.34 19.110 ‡<0.001 0.714 CT + placebo 269.57±18.68 **294.71±27.18 CoQ10 271.00±16.71 270.14±16.49 Placebo 266.14±13.26 267.76±10.17 Chest press (kg) mean±standard deviation CT + CoQ10 23.78±1.70 **31.38±2.98 26.933 ‡<0.001 0.788 CT + placebo 23.51±3.43 ***31.73±3.05 CoQ10 24.65±2.05 24.87±2.01 Placebo 24.52±2.17 24.66±2.79 Lateral pull down (kg) mean±standard deviation CT + CoQ10 22.70±1.78 ***26.01±1.43 17.111 ‡<0.001 0.691 CT + placebo 22.27±2.55 ***25.92±1.76 CoQ10 21.76±2.31 22.29±2.97 Placebo 20.91±2.40 21.47±2.19 Groups Baseline Follow-up Chi- Square p-value ES Leg extension (kg) median (Q1-Q3) CT + CoQ10 12.00(11.61-13.36) *16.87(15.88-17.42) 16.869 †0.001 0.578 CT + placebo 12.41(10.90-13.33) *16.87(15.88-18.62) CoQ10 12.86(12.41-13.33) *12.86(12.86-16.87) Placebo 12.41(11.61-13.33) 12.00(12.00-13.33) Lying leg curls (kg) median (Q1-Q3) CT + CoQ10 12.00(11.61-12.86) *16.36(16.36-17.42) 21.395 ‡<0.001 0.766 CT + placebo 12.41(10.90-13.33) *17.42(16.87-18.62) CoQ10 12.00(11.61-13.33) 12.00(12.00-13.33) Placebo 12.00(11.25-13.33) 12.00(11.61-12.86) * p-value<0.05, ** p-value < 0.01, *** p-value<0.001, by paired-samples t test and Wilcoxon; † p-value < 0.01, ‡ p-value<0.001, by analysis of variance, Kruskal-Wallis, analysis of covariance tests Concurrent training and CoQ10 in Multiple Sclerosis Eur J Transl Myol 33 (2) 11253, 2023 doi: 10.4081/ejtm.2023.11253 - 5 - then 1RM was estimated using the Brzycki formula (21). During all tests participants were verbally encouraged to give their maximum effort. Dietary analysis Dietary information was collected during the first and last study week using a 24-hour food recall questionnaire for three days. Data was analysed using Nutrition 4 software (First Databank, San Bruno, CA, USA). Statistical analysis Sample size (n=28) was estimated using G*Power software v3.1.9.4, with alpha coefficient of 0.05, statistical power of 0.80, and effect size of 0.5, based on previous research. All analyses were conducted using SPSS software (Statistical Package for Social Sciences Chicago, IL, USA) version 20.0. Normal distribution for continuous variables was explored through Shapiro-Wilk test. Changes for BDNF, NGF, timed up and go, 6-min walk, chest press, lateral pull down, leg extension, and lying leg curls between baseline and follow-up were analysed through paired-samples t test and Wilcoxon. The analysis of variance (ANOVA), Kruskal-Wallis, analysis of covariance (ANCOVA) tests were used to compare groups. The LSD and Gamese-Howell tests were used for post hoc comparisons were necessary. Results were considered statistically significant when p <0.05. Results Participants’ demographic and clinical characteristics are shown in Table 1. There was no significant difference within or between groups for daily calorie intake (Table 2). CT+CoQ10 and CT+placebo groups showed significant improvements in TUG (p<0.01), 6MW (p<0.01) and on 1RM loads for chest press (p<0.01), lateral pull down (p<0.01), leg extension (p<0.01), and lying leg curls (p<0.01). CoQ10 group showed a significant improvement only in 1RM leg extension (p<0.05). NGF and BDNF levels did not change for any group (Table 2). All indicators of functional capacities improved at post intervention for CT+CoQ10 and CT+placebo groups compared to CoQ10 and placebo groups. There was a significant difference (p=0.011) in TUG between CT+CoQ10 and CT+placebo, with greater changes for CT+placebo than CT+CoQ10 (Figure 2). Discussion The present study aimed to investigate the effects of eight weeks of CT and CoQ10 supplementation, alone or combined, on physical function, serum BDNF and NGF levels in people with MS. As our main result, CT with or without CoQ10 supplementation, significantly improved physical capacity in MS patients, without changes in NGF and BDNF. Our results are in agreement with previous studies showing that CT improves physical function in patients with MS and might help to manage the negative effects of MS on physical disability and quality of life.22,23 Similarly to our study, Grazioli et al.17 reported that 12 weeks of CT significantly improved TUG and 6MW test in patients with MS. Moreover, Bahari et al.24 reported that eight weeks of CT increased strength and balance in patients with MS. Resistance training has been introduced to improve muscle function, specially for its effects on neural adaptations.25 Increasing lower limbs strength might help to counteract motor fatigue and affects sensory and peripheral nerve pathways or both, leading to improvements in walking speed, endurance and economy.26 Another important effect of resistance training in MS is the increase in maximal neural drive and neural plasticity.27 The combination of increased motor units recruitment, movement economy, reductions on inhibitory inputs from alpha motor neurons can be among the factors responsible for increasing muscle adaptations observed in the present study.25 One factor that might have mediated functional improvements was balance. There is a direct and significant relationship between lower body muscle strength and balance, such that muscle weakness leads to reduced balance and increased risk of falling.28 Fig 2. Indicators of functional capacities Concurrent training and CoQ10 in Multiple Sclerosis Eur J Transl Myol 33 (2) 11253, 2023 doi: 10.4081/ejtm.2023.11253 - 6 - In the present study muscles strengthening due to both resistance training and cycling,29 might have impact balance in these patients. Specifically, resistance exercises might improve balance in MS patients by reducing muscle spasms and sensory disturbances.30 While previous authors found positive effects of cycling in MS,31–34 the mechanism are not fully understood, but might be associated with general improvements in muscle function and physical fitness.32–34 Lower limb muscle strength is related to walking speed and is an important predictor of motor performance in MS patients.35 Resistance exercises has been shown to improve walking kinematics in persons with MS,36 leading to improvement in the performance of 6-min walk test. Moreover, exercise has been shown to increase endorphin levels and improvement psychological factors, which could influence fatigue and improve motor performance.37 Regarding neurotrophic factors, Abbaspoor et al.38 showed that BDNF levels did not change after eight weeks of exercise training. Similarly, Khademosharie et al.39 showed that CT did not cause significant differences in NGF and BDNF levels of patient with MS. However, different from the present findings, previous studies demonstrated that CT increased BDNF levels in patient with MS.40,41 It is difficult to explain this divergence, since the mechanism involved in exercise-induced BDNF concentration is not well known. These differences and inconsistencies might be due to the type and intensity of exercise, the length of the training period, differences in research samples, supplementation dose and duration. Although the benefits of CT are of clinical importance and reinforce previous findings, a major novelty of the present study is the combined supplementation of CoQ10, which has been hypothesized to reduce inflammation and oxidative stress in MS patients.42 Contrary to our hypothesis, there was no benefit in supplementing CoQ10 in the present study, alone or combined with CT, in physical function and NGF and BDNF levels. Based on these findings, CT should be recommended to help in MS management specially for its potential benefits for improving physical function, but this was not the case for CoQ10 supplementation. Low dose CoQ10 supplementation (200 mg daily) or short duration of CoQ10 supplementation period (eight weeks) may have limited the possibility of observing CoQ10 effects on motor abilities and neurotrophic factors. Therefore, longer intervention periods and higher CoQ10 doses should be further investigated in future research. The absence of changes in NGF and BDNF levels may be due to the small sample size. Although we conducted an a priori analysis for samples size, we could not exclude the possibility of type II error in the present study. Consequently, studies with larger samples might be needed to corroborate our findings. Other limitations that can be mentioned in this research are: the lack of precise control of activities outside the training protocol and drugs used by these patients. List of acronyms 1RM – one repetition maximum 6MW - 6-min walk ANCOVA – analysis of covariance BDNF – brain derived neurotrophic factor CoQ10 – Coenzime Q19 CT - concurrent training MS – multiple sclerosis NGF – nerve growth factor TUG - timed up and go Contributions of Authors Conceptualization, AHH and AA; methodology, AHH, AA, RA, KN, BBR, HS; formal analysis, AHH, AA, RA, KN, BBR, HS; writing—original draft preparation, AHH, AA, AC, RA, KN, BBR, HS, DS and PG —review and editing, AHH, AA, AC, RA, KN, BBR, HS, DS and PG; visualization, AHH, AA, AC, RA, KN, BBR, HS, DS and PG. Authors approved the final typescript. Acknowledgments We thanks all the participants of the study. Funding The authors received no specific funding for this work. Conflict of Interest The authors declare no financial, personal, or other conflicts of interest. Ethical Publication Statement We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this report is consistent with those guidelines. Corresponding Author Paulo Gentil, Av. Esperança, s/n - Chácaras de Recreio Samambaia, Goiânia - GO, 74690-900 – Brasil. Phone/Fax: +55 62 3521-1141 ORCHID iD: 0000-0003-2459-4977 E-mail: paulogentil@hotmail.com E-mails and ORCID iD of co-authors Amir Hossein Haghighi: ah.haghighi@hsu.ac.ir ORCID iD: 0000-0002-7258-9737 Amin Ahmadi: amin.ahmadi83@gmail.com Antonio Carotenuto: carotenuto.antonio87@gmail.com ORCID iD: 0000-0002-1574-9693 Roya Askari: r.askari@hsu.ac.ir ORCID iD: 0000-0003-4331-2293 Karim Nikkhah: nikkhahk@mums.ac.ir Behnam Bagherzadeh-Rahmani: b.bagherzadehrahmani@hsu.ac.ir ORCID iD: 0000-0001-9900-0833 Hadi Shahrabadi: h.shahrabadi@gmail.com ORCID iD: 0000-0001-8404-6927 Daniel Costa Souza: daniel_souza86@hotmail.com ORCID iD: 0000-0003-0626-1466 mailto:paulogentil@hotmail.com mailto:ah.haghighi@hsu.ac.ir mailto:amin.ahmadi83@gmail.com mailto:carotenuto.antonio87@gmail.com mailto:r.askari@hsu.ac.ir mailto:nikkhahk@mums.ac.ir mailto:b.bagherzadehrahmani@hsu.ac.ir mailto:h.shahrabadi@gmail.com mailto:daniel_souza86@hotmail.com Concurrent training and CoQ10 in Multiple Sclerosis Eur J Transl Myol 33 (2) 11253, 2023 doi: 10.4081/ejtm.2023.11253 - 7 - References 1. 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Submission: February 12, 2023 Revision received: March 7, 2023 Accepted for publication: March 7, 2023 Results