The effects of alpha lipoic acid on muscle strength recovery after a single and a short-term chronic supplementation - a study in healthy well-trained individuals after intensive resistance and endurance training

In competitive sports, the time span needed for muscle recovery plays a decisive role. The aim is to reduce this time period to a minimum to set new training impulses as quickly as possible. Recovery in sports is a multifactorial process that can be measured in sports medical biomarkers such as the kinetics of muscle damage or inflammatory processes and in applied sports science performance tests such as maximum strength tests [1‐3].

After intensive concentric-eccentric training, the stressed muscles are damaged. This is initiating physiological restructuring processes in the body. Investigations have shown that after intensive strength training [4], endurance training (marathon or longer) [5], extended mountain running [6] and high-intensity interval training [7], training-induced muscle damage (EIMD) is present. Massive EIMD can be also observed after eccentric contractions against high loads [8‐11]. Classical quantitative markers for muscle damage are the increase of creatine kinase (CK) and myoglobin (Myo) serum concentrations. EIMD results also in an inflammatory response of muscle tissue caused by the infiltration of macrophages and can be detected during the entire muscle recovery process [12]. This inflammatory response can be quantitatively analysed by measuring serum concentrations of different cytokines like tumor necrosis factor alpha, (TNF-α), interleukin 1ß, (IL-1ß) and interleukin 6, (IL-6) [13‐15]. Consequently, due to muscle damage and inflammation, shifts in tissue fluids and swelling can occur in the training body regions [16]. In addition to muscle damage and inflammation, intense training can cause oxidative stress due to increased radical formation of hydrogen peroxide (H₂O₂), superoxide (O₂⁻), hypochlorous acid (HOCl) and nitric oxide (NO⁻) [17]. To counteract an inflammatory response and oxidative stress, the supplementation of substances with anti-inflammatory and antioxidant capabilities is usually practiced after physical exercise. One of these substance is alpha lipoic acid (ALA) [18].

ALA has different functions in the human metabolism. ALA is part of the multienzyme complex of pyruvate dehydrogenase, alpha-ketoglutarate and branched alpha-keto acids [16‐18]. Additionally, ALA has an antioxidant effect. ALA is able to recycle endogenous glutathione, one of the most important antioxidants. It is able also to act as a radical scavenger of hydroxy radicals, hypochlorous acids, peroxide radicals and singular oxygen, as well as to form chelate complexes with metal ions [19‐23].

Antioxidant effects of ALA have been demonstrated in different clinical trials. In alzheimer patients ALA have neuroprotective effects of ALA [24]. Moreover, ALA protects against oxidative injuries in non-neuronal and neuronal tissue [25]. ALA, which is also involved in mitochondrial bioenergetic reactions, has attracted considerable attention as an antioxidant for the treatment of diabetic complications such as retinopathy, neuropathy and other vascular diseases [26, 27]. This has been demonstrated as well in animal models, but also in human intervention studies [28‐30]. Interventions could showed that the use of ALA can reduce the concentration of oxidized LDL (oxLDL) in type 2 diabetes patients [31]. Furthermore, oxLDL is an important parameter in connection with other chronic diseases, oxidative stress and physical activity [32, 33].

Besides antioxidants effects, also anti-inflammatory effects of ALA have been described. ALA is able to inhibit the transduction factor nuclear factor kappa B (NFkB) by modulating mitogen-activated protein kinase (MAPK) via Inhibitor kappa B (IkB). NFkB is one of the main signalling pathways for the activation of inflammatory reactions. If NFkB is inhibited, inflammation can be reduced [34‐38]. Anti- inflammatory activity such as inhibition of c reactive protein (CRP), TNF-α, IL-6, IL8 and IL-10 was observed in type 2 diabetics [39, 40]. Similar effects have been demonstrated in patients with metabolic syndrome [41]. In such patients also effects of ALA on body weight reduction and reduction of body mass index (BMI) are described, which further illustrates effects of ALA on energy metabolism [42, 43].

Even used frequently as a nutrition supplement, information regarding effects of ALA in healthy individuals or in competitive athletes is limited. In competitive sports, the use of protein and carbohydrates preparations against muscle damage and inflammation [44, 45] as well as vitamin C and E preparations as antioxidants is common [46]. Recently, it has been demonstrated that ALA reduces the serum concentrations of creatine kinase after a 90-min endurance load indicating possible protective effects with respect to muscle damage [18]. Data regarding potential protective or pro-regenerative effects of ALA are not available so far.

The aim of this study was therefore to determine effects of ALA supplementation on muscle recovery, inflammation and possible anti-oxidative activities after a one-time resistance training and after a six-day high-intensity training week in well-trained individuals. The specific research questions to be investigated are:

Does a single treatment with ALA after acute exercise increase the ability to recover?

Does a short-term chronic application of ALA during a high-intensity training period effect the ability to recover?

Does the application of ALA after acute and during chronic training protocol prevents the loss of performance?

Seventeen out of 18 volunteers successfully participated in the study. One subject was unable to complete the study for health reasons. The subjects were 23.5 (SD 3.1) years old, 183.06 cm (SD 6.8) tall and weighed 81.5 kg (SD 7.4) at the beginning of the study. The weight was additionally measured after 7 days (T2) and at the beginning and end of the second intervention phase. All anthropometric data are shown in Table 2.

The aim of this study was to investigate whether the application of ALA after acute and during chronic training protocols prevents the training induced loss of performance in athletes.

As a functional parameter for pro-muscle recovery effects of ALA supplementation the individual changes in 1RM BS, were investigated and operationalised. As shown in Fig. 3 the six-day chronic training protocol resulted in a reduction of leg strength, which could be counteracted by ALA supplementation. Even if only a time and time x group difference and no group difference could be observed at time T2 (+ 7 d), a interaction and marginal effect could be observed at time T2 (+ 7 d). This can be taken as an indication for possible pro-recovery effects. Similar effects have been demonstrated for other dietary supplements such as creatine or protein shakes [45, 48, 49].

So far, possible pro-recovery effects after training with ALA supplementation have not been described in the literature. Recent investigations have shown that the application of protein carbohydrate combinations counteracts the training induced loss of performance when administered a single application directly after exercise [45, 50, 51]. This could not be observed in this study for ALA (Fig. 3). Neither the ALA-group, nor the control group experience a significant reduce of performance in the acute training protocol. This may be due to the very high performance level of the participants, which is higher compared to the participants examined in the previous study [45]. However, the significance was only slightly missed (ALA: p = .053; PL: p = .051). Athletes who usually complete five training sessions per week and regularly perform back squats will need a higher load than three sets with 12 repetitions and 70% of the 1 RM as well as three sets with 15 low jumps. Nevertheless, it is not possible to draw conclusions about recovery based solely on the slight effect on the performance and short-term chronic ALA application. The change in performance must be considered in the context of the implied muscle damage and inflammatory response and the effect of ALA application. To investigate the effects of ALA supplementation on skeletal muscle damage in this study two independent parameters, CK and Myo concentrations in response to training, were measured. Both training protocols, the single training load and the six-days repeated training load protocol resulted in a significant increase of serum CK and Myo concentrations, indication skeletal muscle damage (Fig. 4) [8, 52‐54].

As visible in Fig. 4a and b, a short-term chronic supplementation of ALA seems to have a small to moderate positive protective effect on skeletal muscle damage as indicated by our biomarkers (CK: d =. 212, Myo: d = .467). However, it is known that CK serum concentration is a very influenceable parameter and should be used with caution. Therefore, in our study only 14 subjects were considered for evaluation of this parameter. Two further subjects were declared as high responders and were individually evaluated. All individuals whose standard deviation was greater than 3.5 after the Z-transformation at T2 were declared as high responders. In general, high responders are individuals who react very strongly to a training stimulus and therefore do not reflect the general course of certain parameters [55]. Interestingly also in these individuals a clear effect of ALA on CK concentration can be seen (supplemental material, Fig. 4 A2). In addition, it also needs to be highlighted, that a possible protective effect ALA with respect to muscle damage has been also demonstrated by a second independent parameter, Myo (Fig. 4b). Similar to the 1-RM BS, no group difference could be detected at time T2 (+ 7 d). Nevertheless, we believe that due to the similar course and effects in CK, Myo concentration and BS, ALA has a reducing effect on muscle damage in chronic application. These observations are consistent with Morawin et al. who observe similar effects of 10 days ALA supplementation on CK after endurance training [15]. Effects of ALA supplementation on serum CK concentrations have also been shown in disease models, suggesting that ALA has a reducing effect on CK concentration [51].

To investigate the effects of ALA supplementation on training induced inflammation the cytokine serum concentrations of IL-6 and IL-10 were measured as biomarkers. It has been already shown that ALA inhibits the activity of the transcription factor NFkB, resulting in a reduced secretion of pro-inflammatory cytokines such as IL-6 [20, 34]. After the intensive chronic training protocol in our study, we observed that serum concentrations of cytokines, associated with inflammation, are modulated by ALA supplementation. After 6 days of intensive training, the IL-6 concentration in the placebo group increased significantly compared to the ALA group (Fig. 5). This confirms the assumption that ALA may suppress training-induced inflammation. Consequently, no anti-inflammatory response is activated in the ALA group (Fig. 5). After the single training program and application, no significant increase in cytokines was observed in both groups. These even decreased slightly at the time of measurement. This may be due to a possible activation of the cytokines in the tissue and not in the measured blood serum, so that the possible measurement time was not chosen appropriately in this design. The assumption that a reaction can be observed after three hours of exposure is based on various previous studies [45, 51]. Due to the different training design, it may be possible that the inflammatory reactions start at different times.

Like shown in Fig. 5, IL-6 and IL-10 serum concentrations were increased by the 6 days repeated training load protocol. A short-term chronic treatment with ALA could counteracted the increase (Fig. 5). These effects are in agreement to findings in patients with metabolic diseases [39‐41, 43]. In such patient’s treatment with ALA also reduces the serum concentrations of inflammation markers such as IL-6, or TNF-α. In Fig. 5 it is shown that also in healthy young athletes, the training induced increase of IL-6 is inhibited by short-term chronic ALA supplementation whereas in the control group a significant increase of IL-6 could be observed after 7 days (p = .005*). Even if no group difference could be detected, a small to medium effect between the two groups could be determined at T2 (IL-6: d = .587, IL-10: d = .428) and are confirm previous studies. However, the inhibition of IL-6 should be interpreted in relation to the context. A reduction of inflammatory processes is a major goal in treatment strategies for various diseases in order to improve the quality of life and reduce long-term side effects [56‐61]. However, with respect to physical activity the induction of muscle damage and inflammation is an important stimulus to activate molecular mechanisms responsible for an adaptation of the physiological processes, and at the end for the training effect [2, 54, 62‐64]. It is an important challenge to find the right balance between training intensity and the resulting skeletal muscle damage and inflammation. A complete suppression of inflammatory processes in response to physical activity, by anti-inflammatory drugs like ibuprofen or diclofenac has been demonstrated to counteract training adaptations [65, 66]. On the other hand, a too strong stimulation of the inflammatory processes by training in association with muscle damage, can even lead to rhabdomyolysis [67‐70]. In the process of inflammation mediated training adaptations, macrophage formation plays a decisive role and can be divided into two phenotypes [71, 72]. Inflammation-promoting M1 macrophages (eg. IL-6) migrate first into the tissue and contribute decisively to the degradation of necrotic tissue. At the same time, they stimulate the proliferation of myoblasts. This is followed by the immigration of anti-inflammatory M2 macrophages (eg. IL-10) [63], which balance the previously necessary inflammatory reactions and thus promote the recovery of muscle tissue [13‐15]. However, when M1 macrophages are suppressed directly, M2 macrophages are not expressed either. This effect could also be observed in T2 (+ 7 d). However, in the ALA-group not only the training induced increase of IL-6, also the increase of IL-10 serum concentration was inhibited by ALA (IL-6 pre: 5.1 pg/ml (SD 4.7), post: 7.8 pg/ml (SD 10.4); IL-10 pre: 8.5 pg/ml (SD 9.3), post: 11.0 pg/ml (SD 15.5). A typical anti-inflammatory activity of a substance normally results in a suppression of pro-inflammatory cytokines like IL-6 but an increase of the serum concentrations of anti-inflammatory cytokines like IL-10 [63]. This profile could be observed recently in previous studies using protein/carbohydrate supplementation as a pro-regenerative intervention intensive endurance training [45]. However, in this study a chronic six-day training protocol was used to simulate a training camp. The main goal of a training camp is not to improve performance in the shortest possible time, but to increase the load capacity and competition hardness [70]. The suppression of IL-6 and IL-10 could also be reproduced in this study design by short-term chronic ALA supplementation. If all effects on muscle damage, inflammation and performance are considered separately, the individual effects are rather small to moderate. However, the individual parameters in sport are very closely related, so that they cannot be considered individually, but only in combination in the overall context. Even if no clear group difference could be determined, a trend towards the effect of ALA in sport can be identified on the basis of the same courses of the independent parameters. Under this aspect it is remarkable that the suppression of training-induced IL-6 and IL-10 by ALA is very effective and this is reproducible in the reduced loss of performance. In competitive sports these small differences can be very decisive for victory and defeat.

One of the major pharmacologic activities of ALA discussed, are a high anti-oxidative capacity [27, 39, 73]. Therefore, in this study effects of ALA on markers for oxidative stress were analysed. As shown in Fig. 6, the biomarker for oxidative stress, oxLDL, was not increased by the chronic training protocol indicating that this training protocol may not be suitable to induce chronic oxidative stress and/or that our participants are too well trained and compensate this stress. Therefore, it was also not possible in this experimental design to investigate potential anti-oxidative effects of ALA. Our training protocol includes resistance, but also endurance training. With the focus on anti-oxidative capacity of ALA in training, it would be more suitable to use a high intensity endurance training protocol for 6 days. However, the focus of this study was on skeletal muscle recovery and maintenance of performance. Based on the observations, it cannot be excluded that ALA also has positive effects in sports through antioxidant activities, but this aspect seems to be less relevant in this study design. Nevertheless, follow up studies should focus also on the effects of ALA treatment in the context of physical activity, especially in long-term treatment over several weeks.

In summary, the data of our study indicate that ALA may support skeletal muscle recovery in scenarios involving chronic training and treatment and prevent the training related loss in performance. In contrast, we did not find any significant effects of ALA in acute training and treatment scenarios. These results suggest also that ALA treatment needs to be chronically to result in training-supporting effects. This is also indicated by our biomarkers for skeletal muscle damage and inflammation.

Regarding possible beneficial effects of ALA in training adaptation it is important to figure out that a district-level of skeletal muscle damage is required to activate molecular mechanisms that lead to training adjustments [74]. Chronic application of ALA may negatively influence this adaptation if the training goal is to improve performance. However, long-term training planning and periodization is based not only on performance improvement, but also on maintaining and improving the hardness of competition. Especially sports, which have competitions over several days, must maintain their performance as good as possible. In this context, hard training weeks or training camps are often held to simulate the competition phases. In this context, chronic ALA supplementation may be useful to maintain performance. Our study design could show first indications and trends that ALA can have a positive effect on maintaining performance and reducing muscle damage and inflammation.. In which sports or scenarios ALA can be usefully applied must be determined in further studies. We conclude that short-term chronic ALA supplementation can support muscle recovery effects and prevents the training induced loss of performance in a specific training or competition phase, in very well-trained athletes. However, for general recommendations, further investigations in different training scenarios and in athletes with different performance, are necessary, also to identify underlying molecular mechanisms. The application time of ALA may also need to be extended in order to achieve more distinct courses and results.