Τρίτη 20 Οκτωβρίου 2015

Benefits of dietary phytochemical supplementation on eccentric exercise-induced muscle damage: Is including antioxidants enough?

Benefits of dietary phytochemical supplementation on eccentric exercise-induced muscle damage: Is including antioxidants enough?


doi:10.1016/j.nut.2015.02.014
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Highlights

•
Dietary phytochemical supplementation may positively modulate eccentric muscle damage.
•
Phytochemical effectiveness on muscle damage may depend on factors of the food matrix.
•
Antioxidant phytochemicals may be not sufficient for the strategy's effectiveness.

Abstract

The purpose of this review was to critically discuss studies that investigated the effects of supplementation with dietary antioxidant phytochemicals on recovery from eccentric exercise-induced muscle damage. The performance of physical activities that involve unaccustomed eccentric muscle actions—such as lowering a weight or downhill walking—can result in muscle damage, oxidative stress, and inflammation. These events may be accompanied by muscle weakness and delayed-onset muscle soreness. According to the current evidences, supplementation with dietary antioxidant phytochemicals appears to have the potential to attenuate symptoms associated with eccentric exercise-induced muscle damage. However, there are inconsistencies regarding the relationship between muscle damage and blood markers of oxidative stress and inflammation. Furthermore, the effectiveness of strategies appear to depend on a number of aspects inherent to phytochemical compounds as well as its food matrix. Methodological issues also may interfere with the proper interpretation of supplementation effects. Thus, the study may contribute to updating professionals involved in sport nutrition as well as highlighting the interest of scientists in new perspectives that can widen dietary strategies applied to training.

Keywords

  • Phytochemicals;
  • Eccentric exercise;
  • Muscle damage;
  • Strength loss;
  • Delayed-oneset muscle soreness;
  • Oxidative stress;
  • Inflammation

Introduction

Eccentric muscle action involves the stretching of skeletal muscle while producing strength and serves primarily to slow down or halt a movement. This type of muscle action comprises a variety of movements typically present in exercises and daily activities, such as lowering a weight, stepping down a slope, or abruptly stopping and changing direction [1] and [2]. However, unaccustomed and repeated eccentric muscle actions may result in muscle damage, inflammation, and oxidative stress. These events often are accompanied by loss of muscle strength and a set of symptoms referred as delayed-onset muscle soreness (DOMS) [1], [2], [3], [4], [5], [6] and [7].
After the so-called eccentric exercise-induced muscle damage (EEIMD) [2], [5] and [8], muscle weakness and DOMS may last a few days (typically 5–7 d) and their magnitude is not exacerbated by effort repetition [3], [4], [6], [7] and [8]. Nevertheless, among athletes, it is usual to search for strategies, including pharmacologic ones, to alleviate muscle discomfort and impairment of performance quality. However, the effectiveness of most of these resources is controversial, with some being potentially unfavorable to adaptive responses to training [5], [6] and [8].
It has been proposed that the slow recovery of muscle strength and DOMS are partially due to the action of reactive molecules and/or inflammatory mediators released in the damaged muscle [9], [10] and [11]. However, it is known that local changes in oxidation-reduction (redox) homeostasis and inflammatory events are part of the process of muscle repair and regeneration [2], [5], [8] and [11]. Despite the apparent paradoxes, the intake of antioxidant-rich food and beverages could have a positive effect on muscle recovery after exercise. Although there is no consensus on the benefits of antioxidant micronutrient supplementation [2], there is evidence that dietary phytochemicals with antioxidant and anti-inflammatory properties modulated muscle symptoms associated with EEIMD [2] and [12]. However, favorable effects were limited in other works [13] and [14], thus highlighting the importance of identifying specific phytochemical-based strategies that can actually improve muscle recovery after exercise [2]. Therefore, the purpose of this review was to critically discuss studies that investigated the effects of supplementation with dietary antioxidant phytochemicals on recovery from EEIMD.

Eccentric exercise-induced muscle damage: A sequence of events

The etiology of EEIMD has been long discussed. It has been proposed that it would result from excessive stretching and ruptures of myofibril filaments [1] and [4] or a failure in the excitation-contraction coupling system during muscle action [15]. However, there is controversy as to which of the mechanisms occurs initially, triggering subsequent damage [1]. Despite that, considering the sequence of events, two natures of EEIMD stand out: the initial damage, related to the mechanical stress of contraction, and the secondary damage, related to later events of metabolic origin (i.e., loss of the intracellular calcium homeostasis, oxidative stress, and inflammation) [1], [9], [15], [16] and [17].
Figure 1 describes a proposed sequence of events following EEIMD, including inflammatory and oxidative responses as well as DOMS symptoms. Muscle weakness seems to be the most immediate functional consequence of EEIMD [1], [8] and [17]. After a fast recovery within 2 to 3 h after exercise, muscle strength restores gradually and may remain depressed for a few days or even weeks, depending on the degree of the damage [3], [4], [8] and [13]. Throughout this period, structural damage may progress, together with inflammatory events that precede tissue repair and regeneration [8], [11], [18] and [19].
Fig. 1.
 
Proposed sequence of events after eccentric exercise-induced muscle damage. 1. Initial eccentric damage (i.e., myofibrillar and/or to E-C coupling elements) results in an immediate decrease in muscle strength, which can lead to membrane damage, as indicated by increased efflux of cytosolic proteins and uncontrolled Ca2+ release from the sarcoplasmic reticulum [1] and [8]; 2A. Damaged muscle fibers release IL-1β and TNF-α proinflammatory cytokines that activated endothelial cells, which in turn express cell surface adhesion molecules, release chemoattractants and proinflammatory cytokines (e.g., IL-6, IL-8); 2B. All those inflammatory mediators may prime and/or attract phagocytic cells toward the injury site [11], [18] and [19]; 3. In the first few hours after injury, neutrophils and monocytes/M1 macrophages progressively accumulate in the exercised muscle, reaching their peak concentration at about 24 and 48 h postinjury, respectively, and then declining in number [3], [8] and [19]. At the injury site, those cells help to remove and degrade damaged tissue by engulfing cellular debris and releasing proteases, inflammatory cytokines, and ROS/RNS [8], [11], [18] and [19]; 4. Proteolytic systems promote the degradation of myofibrillar proteins [8]. 5. ROS/RNS may lead to activation of NF-κB that can mediate the expression of inflammatory cytokines, which may in turn induce further NF-κB activation [11], [18] and [19]; 6. Despite contributing to the early inflammatory stages after injury, some molecules (such as IL-1β, IL-6, TNF- α, and PGE2, as well as NF-κB) seem to play important roles in muscle regeneration and remodeling [8], [11] and [19]; 7. Muscle damage may also be followed by DOMS that seems to be associated with a rise in [Ca2+]i and/or muscle inflammation; 8. After reaching their peak level, M1 macrophages are replaced by nonphagocytic M2 macrophages, whose concentration peaks at about 96 h and may remain elevated for several days postinjury [3], [11] and [19]. M2 macrophages release anti-inflammatory cytokines and growth factors and can contribute to tissue repair and regeneration [11] and [19]. Proliferation of satellite cells is involved in muscle regeneration process [8] and [19]; 9. The time to the full recovery of the muscle depends on the severity of the initial damage. [Ca2+]i, intracellular calcium concentration COX, cyclooxygenase; CK, creatine kinase; DOMS, delayed-onset muscle soreness; E-C, excitation-contraction; IL, interleukin; NF, nuclear factor; PGE2, prostaglandin E2; ROS/RNS, reactive oxygen and nitrogen species; SR, sarcoplasmic reticulum; TNF, tumor necrosis factor; SACs, stretched-activated calcium channels.
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The mechanisms involved in the secondary muscle damage are unclear. Some argue that, in the process of removing tissue fragments, metabolic products from activated phagocytes, including reactive oxygen and nitrogen species (ROS/RNS), would occasionally reach intact structures and, thus, contribute to additional damage and delayed recovery of muscle strength [9], [11], [17] and [19]. Additionally, EEIMD is frequently followed by DOMS, with intensity of discomfort usually peaking between 24 and 72 h postexercise [6] and [7]. DOMS symptoms may include pain, tenderness, swelling, and stiffness [1], [6], [7] and [9] and despite being discussed for decades, they are not completely understood yet. Pain and tenderness would be triggered by the presence of locally released chemicals [4], by the sensitization of muscle nociceptors by tissue breakdown products [1], or by the activation of inflammatory factors present in the epimysium before exercise [10]. Muscle swelling would result from fluid accumulation related to the inflammatory response that follows the damage [1], [4] and [6]. Stiffness has been attributed to the swelling of damaged tissue, local contratures, or both, elicited by an increase in myoplasmic calcium concentration, as a result of damage to membrane systems and/or by stretched-activated calcium release [1], [4] and [7] (Fig. 1).

Characteristics of the studies selected for discussion and critical analysis of methodological aspects

Table 1 shows a descriptive summary of 14 studies—published between 2003 and 2014—that investigated the effect of dietary phytochemical supplementation on muscle damage, oxidative stress, and inflammation markers after eccentric exercise [2], [12], [13], [14], [20], [21], [22], [23], [24], [25], [26], [27], [28] and [29]. One work involving eccentric training [30] (not included in Table 1) was also discussed. Among the studies, 6 were crossover trials [2], [12], [21], [25] and [27] and 10 were parallel-fashion studies [13], [14], [20], [22], [23], [24], [26], [28] and [29]. All studies, except for two [20] and [26], were randomized and placebo-controlled, and of these, 71% were double-blind [13], [14], [21], [22], [23], [24], [25], [27], [28] and [29], thus meeting the main criteria of the gold standard for the evaluation of interventions [31].
Table 1. Effects of dietary phytochemical on muscle damage, oxidative stress, and inflammation markers after eccentric exercise in humans
StudyParticipants' sex (N) age (y)Treatment groupsEccentric exerciseSampling time pointsMain results
Connolly et al. [12]M (14)
22 ± 4		Tart cherry juice (350 mL, 600 mg total phenolic∗) or PLA; 2 x /d for 8 d(Day 3 of treatment)
40 (2 × 20) MEMA of the elbow flexors; ROM: 130°–0°		Pre- and 24, 48, 72, and 96 h postexerciseMIS: <↓ with SUPL vs. PLA from 24–96 h†,‡
PMP: < with SUPL vs. PLA‡
ROM (elbow): ↓ ≅ between groups from 24–96 h
MT: ↑≅ between groups from 24–96 h
Trombold et al. [21]M (16)
24.2 ± 1.4		Pomegranate extract drink (500 mL, 650 mg total phenolics∗) or PLA; 2 x /d for 9 d(Day 5 of treatment)
40 (2 × 20) MIEMA of the elbow flexors (40°.s−1); ROM: 120°–0°		Pre- and 2, 24, 48, 72, and 96 h postexerciseMIS: <↓ with SUPL vs. PLA at 48 and 72 h
PMP: < with SUPL vs. PLA drink at 2 h
CK§: ↑≅ between groups from 2–7 h
Mb§: ↑≅ between groups from 2–7 h
IL-6§ and CRP§: ↔
O'Fallon et al. [22]M (30)
18–25		Quercertin (1000 mg) via energy bar, vitamin C (20 mg), and vitamin E (14 mg) (n = 15) or PLA (n = 15); 1 × /d for 13 d(Day 8 of treatment)
48 (2 × 24) MEMA of the elbow flexors; ROM: 120°–0°		Pre and 0 h (MIS), 24, 48, 72, 96, and 120 h postexerciseMIS: ↓≅ between groups from 0–120 h
PMP: ≅ between groups from 24–96 h
ROM (elbow): ↓≅ between groups from 24–96 h
AC: ↑≅ between groups from 24–120 h
CK§: ↑≅ between groups from 48–120 h
IL-6§; CRP§: ↔
Goldfarb et al. [13]M (26)
F (15)
18–35		Juice Plus+® (fruit,
vegetable, and berry juice powder concentrates) (n = 21) or PLA (n = 20); 6 capsules/d for 32 d
The daily serving of Juice Plus+® provided 180 IU vitamin E, 276 mg vitamin C, and 7.5 mg β-carotene		(Day 29 of treatment)
48 (4 × 12) MIEMA of the elbow flexors (20°.s−1); ROM: 100°–0°		Pre and 0, 2, 6, 24, 48, and 72 h postexerciseMIS: ↓≅ between groups from 0–72 h
PMP: ≅ between groups from 24–72 h
ROM (elbow): ↓≅ between groups from 0–72 h
CK‖: ↑≅ between groups from 24–72 h
MDA‖: ↑ with PLA vs. pre from 24–72 h‡
Protein carbonyls‖: ↑with PLA vs. pre from 6–72 h†
GSSG/TGSH: ↑≅ between groups at 0 h; ↑ with PLA at 6 h
Black et al. [23]Supplement group:
M (3)
F (14)
20.9 ± 0.6
PLA group:
M (3)
F (14)
21.1 ± 0.7		Raw ginger (2 g; 7.3 mg/g gingerol and 2.2 mg/g shogaol) or PLA; 1 × /d for 11 d(Day 8 of treatment)
18 (3 × 6) MEMA of the elbow flexors; 120% of the 1-RM through a full ROM		Pre- and 24, 48, and 72 h postexerciseMIS: ↓≅ between groups from 24–72 h
PMP: < with SUPL at 24 h
ROM (elbow): ↓≅ between groups from 24–72 h
Arm volume: >↑ with SUPL vs. PLA from pre- to 72 h†
PGE2: ↔
Phillips et al. [24]M (40)
18–35		Quercetin (200 mg), hesperidin (100 mg), DHA (800 mg), vitamin E (300 mg) (n = 20) or PLA (n = 20); 1 × /d for 14 d(Day 7 of treatment)
60 (3 × 10) EMA of the elbow flexors; 80% of the eccentric 1-RM		Before treatment (baseline), pre- and 72 and 168 h postexercisePMP: ≅ between groups at 72 h
ROM (elbow): ↓≅ between groups at 72 h
CK§ and LD§: ↑≅ between groups at 72 h
ALT‖: ↑≅ between groups at 72 and 168 h
IL-6§: <↑ with SUPL vs. PLA between pre- and 72 h
CRP§: <↑ with SUPL vs. PLA between baseline and 72 h
O'Connor et al. [14]M (20)
F (20)
18–35		Grape powder (46 g, 176 mg total phenolics∗) diluited with water (n = 20) or PLA (n = 20); 1 × /d for 45 d(Day 43 of treatment)
18 (3 × 6) MEMA of the elbow flexors; 120% of the concentric 1-RM		Pre- and 24 and 48 h postexerciseMIS: ↓≅ between groups from 24–48 h
PMP: ↔
ROM (elbow): ↔
Arm volume: ↔
Trombold et al. [25]M (16)
21.9 ± 2.4		Pomegranate extract drink (250 mL; 1979 mg/L tannins, 384 mg/L anthocyanins, and 121 mg/L ellagic acid derivatives) or PLA; 2 ×/d for 15 d(Day 8 of treatment)
60 (3 × 20) MIEMA of the elbow flexors (40°.s−1); through a full ROM
60 (6 × 10) MIEMA (knee extensor muscles); 110% of the 1-RM; through a full ROM		Pre- and 2, 24, 48, 72, 96, and 168 h postexercise(Elbow flexors)
MIS: <↓ with SUPL vs. PLA from 2–168 h†
PMP: <with SUPL vs. PLA from 2–168 h† and during 48–72 h‡
(knee extensors)
MIS: ↓≅ between groups from 2–168 h
PMP: ≅ between groups from 2–72 h
Kerksick et al. [20]M (30)
20 ± 1.8		EGCG® (1800 mg: 98% total phenolics∗ and 50% EGCG) (n = 10), NAC (1800 mg) (n = 9), or PLA (n = 10); 1 × /d for 14 d before exercise100 (10 × 10) MIEMA of the knee extensors (30°.s−1); ROM: 0°–80° of knee flexionPre- and 6 and 24 h postexercisemRNA levels for MURF1, UBE3 B, and m-calpain)#: ↑≅ between the EGCG, NAC, and PLA groups at 6 and 24 h
Kerksick et al. [26]M (30)
20 ± 1.8		EGCG (1800 mg: 98% total phenolics∗ and 50% EGCG), NAC (1800 mg), or PLA; 1 × /d for 14 d before exercise100 (10 × 10) MIEMA of the knee extensor (60°.s−1); ROM: 0°–80°Pre- and 6, 24, 48, and 72 h (except for biopsy)MIS: ↓≅ between groups at 6 and 24 h
PMP: ≅ between groups at 6, 48, and 72 h; < with the EGCG and NAC groups compared with PLA at 24 h
CK§: ↑≅ between groups from 6–48 h
LD§: ↑ ≅ between groups at 6 h
8-isoprostane§:↔
SOD§: ↔
TNF-α§: ↔
McLeay et al. [2]F (10)
22 ± 1		Blueberry-based beverage (blueberry, banana, and apple juice; 168 mg total phenolics∗) or PLA (banana and apple juice; 29 mg total phenolic∗); 10 and 5 h before and 0, 12, and 36 h postexercise (n = 10)300 (3 × 100) MIEMA of the knee extensor (30°.s−1); ROM: 0°–60°Pre- and 12, 36, and 60 h postexerciseMIS: <↓ with SUPL vs. PLA from 12–36 h‡
PMP: ≅ between groups from 12–60 h
CK§: ↑≅ between groups from 12–36 h
Plasma radical ROS-generating potential: ↑≅ between groups from pre to 12 h; ↓ with SUPL vs. PLA from 12–60 h‡
Protein carbonyls‖: ↑≅ between groups from pre- to 12 h; ↓≅ between groups from 12–60 h
FRAP ‖:↑ with SUPL vs. PLA from pretreatment to 60 h postexercise‡
IL-6‖: ↑ ≅ between groups from 12–60 h
Udani et al. [27]M (5)
F (5)
27.7 ± 8		BounceBack® or PLA; 2 capsules/d for 30 d before exercise (n = 10)
The daily serving of BounceBack® provided 421 mg tumeric extract (curcumin-rich), 90 mg phytosterols, 6 mg Japanese knotweed extract (20% resveratrol), 20 mg vitamin C, and 258 mg proteases		Maximal number of quadriceps squat in a 5-min periodPre- and 0 (except for PMP), 6, 24, 48, and 72 h postexercisePMP: < with SUPL vs. PLA at 6 and 48 h
MT: < with SUPL vs. PLA at 24 h
CK‖ and Mb‖: ↑ in both groups from pre- to 72 h, but trended to be lower with BounceBack® vs. PLA from 24–72 h
IL-6‖, TNF-α‖, and CRP‖: ↔
Machin et al. [28]M (45)
22.3 ± 4.1		Pomegranate juice concentrate (30 mL, 650 mg total phenolic∗) diluted with water and/or PLA for 8 d
Supplementation groups:
- (1 × ) pomegranate juice 1 ×/d and PLA 1 ×/d
- (2 × ) pomegranate juice 2 x/d
- PLA 2 x/d		(Day 4 of treatment)
10 sets downhill running (−10% grade) at 200 m/min−1 (2 min/set) followed by bilateral MEMA of the elbow flexors, 100% of the concentric 1-RM; ROM: 130°–0°		Pre- and 2, 24, 48, and 96 h postexercise(Knee extensors)
MIS: <↓ with 1 × and 2 × SUPL vs. PLA from 24–96 h†
PMP: ≅ between 1 × , 2 × SUPL and PLA from 2–48 h
(elbow flexors)
MIS: <↓ with 1 × and 2 × SUPL vs. PLA from 24–96 h†
PMP: ≅ between 1 ×, 2 × SUPL and PLA from 2–48 h
Mb§: ↑≅ between 1 ×, 2 × SUPL and PLA at 2 h
Drobnic et al. [29]Supplement group:
M (9)
32.7 ± 12.3
PLA group:
M (10)
38.1 ± 11.1		Phytosome® (1 g) or PLA, 2 ×/d for 4 d
The daily serving of Phytosome® provided 200 mg curcumin		(Day 3 of treatment) 45 min downhill running (−10% grade) at the anaerobic thresholdPre- and 2 and 24 h postexercise (except for PMP)
PMP: pre- and 48 h		PMP (lower limbs): < with SUPL vs. PLA at 48 h
CK: ↑≅ between groups from pre- to 24 h
FRAP: ↔
Catalase: ↔
Glutathione peroxidase: ↔
CRP: ↑≅ between groups from pre to 24 h
IL-8: ↑ with PLA vs. pre at 2 h
AC, arm circumference; ALT, alanine aminotransferase; AST, aspartate aminotransferase; CK, creatine kinase; CRP, C-reactive protein; DHA, docosahexaenoic acid; EGCG, epigallocatechin-gallate; EMA, eccentric muscle actions; FRAP, ferric-reducing ability of plasma; GSH, reduced glutathione; GSSG, oxidized glutathione; IL, interleukin; LD, lactate dehydrogenase; Mb, myoglobin; MDA, malondialdehyde; MEMA, maximal eccentric muscle actions; MIEMA, maximal isokinetic eccentric muscle actions; MIS; maximal isometric strength; MT, muscle tenderness; NAC, N-acetyl-cysteine; NO•, nitric oxide; 1-RM, one-repetition maximal; PGE2, prostaglandin E2; ↔, no change; PLA, placebo; PMP, perceived muscle pain; ROM, range of motion (position 0° = full limb extension); ROS, reactive oxygen species; SOD, superoxide dismutase; SUPL, supplement; TGSH, total glutathione; TNF, tumor necrosis factor
∗
Expressed as gallic acid equivalents.
†
Treatment effect.
‡
Time × treatment.
§
Serum.
‖
Plasma.
Blood.
#
Muscle.
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Characteristics of the participants

The age range of the participants in the discussed studies was 18 to 35 y. One study included only women [2], whereas four [13], [14], [23] and [27] evaluated individuals of both sexes. In this context, it is important to point out that there may be sex differences regarding the responses to EEIMD. After eccentric exercise, women may show a higher deficit in muscle strength and a lower increase in serum creatine kinase (CK) [32] and muscle soreness than men [33]. Additionally, hormone fluctuations during the menstrual cycle may influence the maximum voluntary force production [34], thus suggesting that information concerning the menstrual cycle of the female participants, during the experimental protocol, may be relevant. One study [2] standardized the menstrual cycle phase during which women performed the eccentric exercise. However, in studies that evaluated both men and women [13], [14], [23] and [27], there was no consideration about controlling variables that might be influenced by sex or about potential limitations of the results in this regard. These methodological issues might have led to biased interpretations of the effects of exercise and phytochemicals on the assessed markers of muscle damage.
Training status may have important effects on muscle damage, inflammation, and oxidative stress markers [3], [8], [30] and [35]. Adaptive responses can be observed after a single bout of eccentric exercise, and the magnitude of the damage is not increased by effort repetition—a phenomenon known as the “repeated bout effect” [3] and [7]. Thus, the homogeneity of the participants' physical activity levels may contribute to the accurate interpretation of the observed results. For instance, muscle leukocyte infiltration after eccentric exercise was higher in sedentary individuals compared with physically active or very active participants not engaged in strength training or other high-force activities [3]. In most studies assessed for this review, the participants were physically active and not trained in resistance-training exercises [12], [13], [14], [20], [21], [24], [26], [27], [28] and [30] or, conversely, experienced in resistance training, aerobic exercises, or both [2], [25] and [30]. However, in one study [22], participants were inexperienced in resistance training, but their level of physical activity ranged from sedentary to recreationally active. One study [23] excluded potential participants involved in moderate to high-intensity resistance training, but did not clearly report the level of physical activity of the selected sample. Therefore, in these studies [22] and [23], a large diversity in physical activity levels among the participants might have influenced the magnitude of muscle damage and, thus, the effects of the supplementation.

Dietary intake assessment

Although 50% of the analyzed studies established the use of nutritional supplements as an exclusion criterion [13], [20], [21], [24], [25], [26] and [30]; only 29% assessed current or usual intake by food frequency questionnaire [14], dietary record [2], or 48-h food recall [20] and [26]. In one study, the diet was standardized during the experimental period [2] and [27], whereas in another one, lists of antioxidant-rich food, whose consumption should be avoided during the research, were provided [2]. Knowledge and control of dietary intake allows for the exploration of the effectiveness of the antioxidant treatment administrated [2]. However, the intentional restriction of antioxidant-rich food throughout the study must be careful at the risk for the effects of the strategy becoming conditioned to situations of antioxidant-poor diets.

Characteristics of the supplements

Regarding the treatments (Table 1), the forms of phytochemical supplementation were drinks based on fresh fruit [2] and [12], dried fruit powder [14], or fruit extract [21], [25] and [28]; capsules with vegetable and fruit [13] or dried rhizome [23] concentrates; capsules with plant extracts [27], [29] and [30]; energy bar with isolated phytochemicals added [22]; and capsules of isolated phytochemicals, whether combined [24] or not [20] and [26] with other substances. Table 2 shows the classification of the major phytochemicals present in the treatments [36]. All supplements contained at least one type phenolic compound. Most of the treatments contained phenolic compounds belonging to the class of flavonoids [2], [12], [13], [14], [20], [22], [24], [26] and [30]. In three studies, the supplements were rich in hydrolyzable tannins [21], [25] and [28]. Other classes of phenolic compounds (i.e., stilbenes [14] and [27], curcuminoids [27] and [29], phenyl alkanones [23], and phenylpropanoids [30]) were also found. Only one study included sterols compounds in the supplement [27].
Table 2. Classification of major phytochemical compounds present in the supplementations used in the studies
Group/classSubclassPhytochemicals∗Studies
Phenolic compounds:
 FlavonoidsCatechinsCatechin, epicatechin[14]
Epigallocatechin-gallate[20] and [26]
Quercetin[14], [22] and [24]
AnthocyaninsPeonidin, cyanidin, malvidin, pelargonidin[2], [12], [13] and [14]
FlavononesHesperidin[24] and [30]
FlavonesLuteolin[30]
 Stilbenes
Resveratrol[14] and [27]
 Fenolic acidsHydroxycinnamic acidsChlorogenic, cumaric, caffeic, and ferulic acids[2], [12] and [13]
 Hydrolyzable tannins
Ellagitannins[21], [25] and [28]
 Curcuminoids
Curcumin[27] and [29]
 Phenyl alkanones
Gingerol (s)/Shogaol (s)[23]
 Phenylpropanoids
Verbacoside[30]
TerpenePhytosterolsBeta-sitosterol, campesterol, stigmasterol[27]
∗
Reference 36 was also consulted.
Table options
In general, the daily amounts of phytochemicals supplied by the treatments seem to have been significant. For instance, the daily polyphenol intake in the Spanish diet was recently estimated between ∼2600 and 3000 mg per person [37]. In the three studies where participants were given drinks made with fresh or powdered fruit, the supplementations corresponded to the daily intake of 800 g of blueberry [2], 100 to 120 units of cherries [12], and 253 g of grape [14]. The daily intake ratios of polyphenols provided by the treatments amounted to 26% [2], 46% [12], and 8% [14] of the Spanish daily intake [37]. Concerning the pomegranate-based supplementations, the ratios of daily polyphenol intake were 25% [28] and 50% [21] and [25] of the Mediterranean diet [37]. Therefore, the use of strategies with phytochemical-rich foods might contribute significantly to the athletes' daily intake of polyphenols.

Eccentric exercise protocols and muscle-damage markers employed

The exercise protocol is a primary determinant of the magnitude of EEIMD [1] and [8]. For example, a larger degree of damage seems to be elicit by single-joint maximal eccentric exercises across a large joint range of motion (ROM) than downhill running at about −8% grade [8]. Almost 80% of the studies used single-joint maximal eccentric muscle actions, mostly employing the elbow flexor muscles (Table 1). Moreover, differences concerning number of repetitions performed, velocity of movement, or muscle group studied, for example, could also explain, at least in part, the diversity of changes observed in the markers of muscle damage, regardless of treatments used (Table 1). Thus, it appears that the effectiveness of a phytochemical supplement may depend on the eccentric exercise performed.
The most common muscle-damage marker used in the studies was muscle pain [2], [12], [13], [14], [20], [21], [22], [23], [24], [25], [26], [27], [28] and [29], followed by concentration/activity of circulating cytosolic proteins, mostly CK [2], [18], [21], [22], [24], [25], [29] and [30], and muscle strength [2], [12], [13], [14], [21], [22], [23], [25], [26] and [28]. Six studies used the measurement of ROM for evaluating muscle stiffness [12], [13], [14], [22], [23] and [24]. In five studies, limb volume/circumference was measured for estimating of the swelling [12], [14], [23] and [24]. Muscle tenderness to palpation was assessed in two studies [12] and [27], whereas only one study evaluated the expression of genes related to muscle proteolysis [20]. This latter variable is not usually used as muscle-damage marker [20] but is likely involved with the recovery from EEIMD [38].
Despite the variety of measurement tools currently used in the study of EEIMD [39], the muscle function measured as force-generation capacity has been considered the most reliable and valid marker of the magnitude of muscle damage [8] and [39]. Other markers of muscle damage (e.g., DOMS, ROM, and concentration of circulating cytosolic proteins) may not always show a good correlation with the muscle functional change after injury [39]. Therefore, caution is necessary in interpreting the results concerning the effects of phytochemical treatment on EEIMD obtained from the use of these indicators.

Effects of the dietary antioxidant supplementations on muscle damage, oxidative stress, and inflammation markers

According to the results of biochemical and muscle-damage markers, benefits were reported for most fruit-based [2], [12], [21], [25] and [28] and plant extracts/rhizome-based [23], [27], [29] and [30] drinks. In these studies, the positive results were attributed mainly to the antioxidant and anti-inflammatory properties of the phytochemicals in the supplements. However, the effects of the interventions on muscle-damage markers were not always in agreement with the changes in blood oxidative stress, inflammation indicators, or both, after exercise [2], [13], [22] and [30]. For example, favorable profiles of muscle damage and blood oxidative stress markers were observed after supplementation with cherry- [12] or blueberry-based drinks [2]. Both cherry and blueberry are rich in anthocyanins, which are known for their superior antioxidant and anti-inflammatory potential [39]. Nevertheless, supplementation with vegetable or fruit concentrate, including anthocyanin-rich berries, did not influence muscle-damage markers, although it improved blood oxidative stress markers [13]. Likewise, consumption of grape-based drink—rich in several phytochemicals, including anthocyanin—did not affect any marker of muscle damage [14] (Table 1). It was proposed that the inefficacy of treatment on muscle-damage markers might have resulted from the decrease in biological activity of the bioactive compounds due to the intestinal and liver metabolism of these compounds [14] and [22], from their interaction with other food constituents, or because they might have been quantitatively insufficient in the target tissues to bring benefits to the muscle damage [14].
Together, these studies suggest that in certain situations, such as EEIMD, factors inherent in the food matrix and plant extracts (e.g., nature, amount and metabolism of phytochemicals, and their interactions) [36], [37] and [40] may influence treatment effectiveness. The presence of bioactive, non-phytochemical compounds also might contribute to the positive effects of supplementation [2] and [40]. However, this interaction is probably complex and might not always be usefull [40]. For instance, the combined supplementation of quercetin, vitamin E, and the fatty acid docosahexaenoic acid (DHA) did not affect changes in muscle-damage markers [24].

Muscle strength

Among the studies that investigated the effects of phytochemical supplementation on muscle strength recovery from EEIMD, positive results were only observed with cherry- [12], blueberry- [2] or pomegranate-based [21], [25] and [28] drinks (Table 1). In these studies, the daily polyphenol amount in the supplements ranged from 650 to 1300 mg. The intake of lower doses might partially explain the lack of benefits of other interventions [14]. The consumption of ∼180 mg/d of polyphenols of grape juice did not influence the recovery of elbow flexion muscles strength in individuals who did not regularly participate in intense physical exercise [14]. However, intake of pomegranate juice providing 650 or 1300 mg/d of polyphenols improved the recovery of elbow flexor [21] and [28] and knee extensor [28] muscle strength in individuals not involved in resistance training. Conversely, in resistance-trained individuals, pomegranate juice consumption providing 1300 mg/d of polyphenols improved strength recovery of the elbow flexor muscles but not of the knee extensor muscles, although both had performed the same exercise volume [25]. The authors proposed that the more prominent strength loss in the upper limbs compared with that in the lower limbs might have favored the therapeutic potential of supplementation and that this difference could be related to inherent characteristics of the knee extensor muscles (i.e., potential protective effect of daily use pattern) or to the inadequate loading during eccentric exercise [25]. Thus, in these studies [14], [21], [25] and [26], the effectiveness of supplementation in muscle recovery appears to have been influenced by different factors, including the daily amount of polyphenols supplied, the muscle group studied, the exercise protocol employed, the participants' training status, or a combination thereof.
Additionally, intrinsic properties of the food matrix also may influence the effect of treatment on muscle recovery. The intake of blueberry-based drink resulted in faster muscle strength restoration than placebo with similar antioxidant capacity [2]. According to the authors, the positive effect of blueberry on strength recovery did not depend on the inherent antioxidant properties of the drink, and other relevant biological activities of anthocyanins (e.g., modulation of gene transcription) might be involved in the benefits of supplementation [2]. However, there is also the possibility that the strategy's effectiveness resulted from interactions between anthocyanins and one or more bioactive constituents present in the blueberry, thus making the effect unique to the food and not to specific phytochemicals [40].

Delayed-onset muscle soreness and muscle proteolytic gene expression

In several of the studies, there was a certain temporal relationship between DOMS and muscle weakness from 24 to 72 h postexercise [2], [12], [13], [21], [22], [23], [25], [26] and [28]. However, the effects of supplementation on DOMS symptoms were not consistent [2], [13], [22], [26] and [28], which seem to agree with the limitations of DOMS for quantifying muscle damage [8] and [39] (Table 1).
The muscle pain was attenuated with cherry juice [12] as well as with capsules of raw ginger [23] and supplements containing curcumin [27] and [29]. Conversely, although rich in anthocyanins, the blueberry-based drink did not affect muscle pain [2], suggesting a potential influence of the food matrix [39] on the strategy's effectiveness on a specific symptom of DOMS. Supplementation with isolated catechins [26] or pomegranate-based drinks [21] and [28] promoted only a slight improvement or no improvement at all in muscle pain. It was assumed that the measure of perceived pain in the elbow flexor muscles may not have been sensitive enough to detect subtle benefits of supplementation, or that the amount of muscle mass that suffered DOMS was small [21]. However, in a later work involving the same muscle group (elbow flexors) and treatment, but with a higher number of eccentric muscle actions, the same authors observed a lower muscle pain with pomegranate drink 48 and 72 h postexercise [25]. It is noteworthy that although both studies [21] and [25] evaluated the elbow flexor muscles, in the placebo trial, strength loss 2 h postexercise was 8% higher in the second study [25], thus suggesting an influence of the exercise protocol in inducing DOMS and possibly on treatment effectiveness. As for muscle tenderness, only supplementation with turmeric extract, phytosterols, and resveratrol [27] promoted a brief improvement. Interestingly, raw ginger treatment resulted in significant larger arm volume than the placebo before and at all time points after exercise. Nevertheless, it appeared that the effect of supplementation did not show a high practical significance (i.e., effect sizes >0.80 SD) [23].
Elbow ROM and arm volume/circumference were not affected by supplementations despite having changed in temporal agreement with the remaining muscle-damage markers [12], [13], [14], [20], [22], [23] and [24] (Table 1). According to one study [12], the ineffectiveness of cherry juice in elbow ROM and muscle tenderness might indicate that the measurements were insensitive to actual differences between supplement and placebo. The authors assumed that the tenderness measurement made only at one site may or the use of a small muscle group during eccentric exercise may have been limiting factors. As for elbow ROM, they suggested that a more damaging eccentric exercise protocol or a large sample size may be required to evaluate the effect of cherry juice intake on this damage marker.
The degradation of damaged myofibrils after eccentric exercise is associated with the activation of proteolytic complexes, such as ubiquitin-proteasome system (Fig. 1). There is evidence that ROS up-regulates the expression of ubiquitin pathway genes in skeletal muscle [41]. However, neither the flavonoid epigallocatechin-gallate (EGCG) nor the antioxidant non-phytochemical compound N-acetyl-cysteine (NAC) affected the increase in intramuscular expression of ubiquitin genes after eccentric exercise [20] ( Table 1). It was assumed that the discontinuity of treatment after the eccentric exercise bout may have prevented that serum and tissue concentrations of EGCG and NAC had remained in effective levels. It was also proposed that the bioavailability of EGCG and NAC limited the amount of antioxidants delivered to tissues [20].

Circulating cytosolic proteins

The amount of circulating cytosolic proteins increased significantly after eccentric exercise in all studies assessing this type of marker [2], [13], [21], [22], [24], [26], [27], [28] and [29] (Table 1). Apparently, this highlights the reliability and validity of this measure as a muscle-damage indicator. Nevertheless, in some of these works, the increase in circulating cytosolic proteins occurred regardless of the improvement in muscle strength recovery promoted by supplementation [2], [21] and [28]. Therefore, measurement of cytosolic proteins may not always clearly reflect the amount of exercise-induced muscle damage [8] and [39] or treatment effects. However, another interpretation could be that the phytochemical-based strategy failed in reducing changes in permeability of sarcolemmal membrane (Fig. 1) despite having attenuated the secondary myofibrillar damage induced by eccentric exercise.
The activity or concentration of circulating cytosolic proteins may be influenced by different factors, including their plasmatic removal, interindividual variability, hydration status, exercise protocol, and training status [39] and [42]. Plasma CK activity, especially, can be improved by the concentration of reduced glutathione (GSH) in the blood. GSH protects against oxidation of the thiol (—SH) groups of CK, preventing enzyme inactivation [43]. It was observed that supplementation with shiitake mushroom extract increased plasma CK activity and improved thiol redox status before exercise [44]. Shiitake mushroom produces l-ergothioneine amino acid, which is capable of neutralizing reactive species and interacting with enzymes associated with the GSH system [44]. Therefore, improvements in blood thiol status promoted by phytochemical-based supplementation [13] might influence CK response during recovery from EEIMD.
One study [30] investigated the effects of lemon verbena extract supplementation (1800 mg/d, 10% verbascoside) on responses of cytosolic proteins in the serum to eccentric training (downhill running, 90 min/d for 21 d). The supplementation occurred during the training period. In the placebo group, the levels of CK and myoglobin were not affected by training, which probably reflected the prior participants' training status (moderately trained) [30]. However, the supplementation reduced the initial values of the activities of aspartate aminotransferase and γ-glutamyltransferase and prevented the increase in alanine aminotransferase activity. Therefore, despite the limitations of these markers concerning muscle damage [39], together these results do not rule out the possibility of phytochemical-rich food providing cell protective effects over a period of eccentric training.

Blood oxidative stress markers

It has been assumed that the primary mechanism for muscle weakness, muscle pain, and membrane integrity damage would be unrelated to blood markers of oxidative stress following eccentric exercise and, thus, the levels of oxidative stress markers in the blood may not be good indicators of EEIMD [13]. In other words, blood oxidative stress markers may not always reflect the muscular redox dynamics after eccentric exercise [13] and [45].
Nevertheless, improvement in antioxidant potential and/or protection against oxidation of lipids and proteins in plasma were observed with blueberry-based drink [2] and vegetable or berry fruit concentrate [13] (Table 1). However, the antioxidant effects may have been partially dependent on the protocol of treatment. According to one study [13], vegetable and berry fruit concentrates prevented the rise in protein carbonyls and malondialdehyde levels from 2 to 72 h postexercise. With blueberry-based drink [2], plasma total antioxidant potential increased significantly between the pretreatment and the 60 h postexercise time point. However, there was a significant increment plasma ROS-generation potential from pretreatment to 12 h postexercise, which was followed by an increased in protein carbonyls level similarly to placebo. Thereafter, plasma ROS-generation potential fell significantly up to 60 h postexercise with only the blueberry drink. Over this time period, protein carbonyl levels also decreased but there was no significant difference between conditions. It is possible that the lack of an early antioxidant protection with the blueberry drink could be in part explained by the short period (∼10 h) of preexercise supplementation. The vegetable or berry fruit concentrate was provided over 28 d before exercise, which probably promoted the required tissue and plasma saturation [36]. However, differences in the physiological and metabolic responses to the exercise protocols used (i.e., upper [13] versus lower limbs [2]) cannot be ruled out.
In the previously mentioned study [30], lemon verbena extract prevented the increase in neutrophils' protein carbonyls and malondialdehyde levels and attenuated the activation status of these cells (decreasing the myeloperoxidase activity, a peroxide-detoxifying enzyme) after a 3-wk eccentric training. The authors concluded that this might represent a protective effect against oxidative stress in neutrophils.

Circulating inflammatory markers

The successful resolution of muscle damage (i.e., optimal degradation of damaged structures and tissue reconstruction) depends partially on the balance between signaling and pro- and anti-inflammatory actions [11] and [35]. However, the relationships between EEIMD and systemic inflammatory mediators responses are not always clear. Factors such as type of effort, training level, time of blood sampling, and alterations in the pool of circulating cytokines may influence these associations [46]. Of the nine studies evaluating blood inflammation markers, only four observed an influence of exercise, especially in interleukin (IL)-6, IL-8, and C-reactive protein (CRP) [2], [20], [21], [22], [23], [24], [26], [27] and [29] (Table 1). The absence of effects of eccentric exercise on inflammatory markers was attributed to the type of protocol used [22], the sample size [27], the possibility of these serum markers not reflecting inflammation under these experimental conditions, a lack of inflammation, or a combination of these factors [21]. It is interesting that all nine studies reported evidence of muscle damage.
The importance of IL-6 response in exercise has been associated mainly with its metabolic and anti-inflammatory effects, although it also has inflammatory actions [47]. One study [2] observed that there is controversy that the increase in circulating IL-6 concentration correlates with skeletal muscle damage. Nevertheless, IL-6 seems to play an important role in muscle differentiation and growth [19]. IL-6 stimulates the release of CRP and IL-10 [48] and [49]. Similarly to IL-6, CRP has anti-inflammatory and inflammatory properties; for example, it facilitates phagocytosis of cell debris and stimulates the release of IL-1, IL-6, IL-8, and tumor necrosis factor-α [48]. IL-10, an anti-inflammatory cytokine, appears to participate in muscle regeneration [19]. IL-8 has inflammatory properties including chemotaxis and the induction of neutrophils degranulation [50] (Fig. 1).
The effects of phytochemical treatments on blood inflammatory markers were reported in two of the discussed studies [24] and [29] (Table 1). Curcumin capsules prevented a transient although significant increase in IL-8 levels after exercise. CRP levels just tended to be lower than placebo at 24 h postexercise [29]. The authors concluded that the anti-inflammatory mechanism of the treatment might be partly associated with suppression of the nuclear factor-κB. Supplements containing quercetin and hesperidin attenuated postexercise changes in IL-6 and CRP levels [24]. It was assumed that these benefits resulted from the anti-inflammatory effects of the supplement, although they seem to have been insufficient to decrease muscle damage. In this study, however, in addition to flavonoids, supplementation further contained another compound with anti-inflammatory properties: the fatty acid DHA [51]. Thus, the effects of supplementation reported by the authors cannot be attributed, at least exclusively, to its phytochemical compounds. Noteworthy is also that neither of the above studies [24] and [29] included muscle strength as a marker of muscle damage [39], which may have limited the observation of potential effects of treatment on the associations between inflammatory and muscle-damage markers. None of the discussed studies assessed IL-10 response to EEIM. However, there is evidence of rising in plasma IL-10 levels after a 2.5-h run in individuals supplemented with blueberry [52].
ROS/RNS act as signals in cellular processes that integrate adaptive mechanisms with acute exercise and training [52]. There are evidences that high-dose supplementation of antioxidant compounds, including nutrients, can impair cellular adaptation to exercise [5] and [53]. However, little is known about the effects of supplementation of phytochemicals with antioxidant and anti-inflammatory properties in immediate and long-term body adaptations to eccentric exercise. One study [30] demonstrated that eccentric training increased basal activity of the antioxidant enzymes glutathione peroxidase, glutathione reductase, and catalase in neutrophils and decreased circulating levels of IL-6 and IL-1β, which was consistent with adaptive mechanisms of the antioxidant and immune systems. The authors highlighted that lemon verbena extract did not negatively influence the adaptive responses and promoted further decrease in IL-6 production in the cell. Therefore, regular dietary phytochemical intake seems to be beneficial rather than harmful to adaptative responses to exercise.

Conclusion and future perspectives

Supplementation with dietary phytochemicals seems to have the potential to positively modulate EEIMD symptoms. However, it is unclear whether these benefits involve primarily antioxidant mechanisms. According to several reports, it appears that the effects of this strategy result from complex interactions between a number of factors, including type and concentration of phytochemicals compounds, dose and timing of intervention, metabolism and biological activities of phytochemicals, presence of other bioactive compounds, and influence of the factors inherent in the food matrix. Additionally, methodological issues such as dietary intake, training status, exercise protocol, and type of muscle-damage marker used also may influence the results. Thus, the presence of the antioxidant phytochemicals in the supplement may be an essential part, but not sufficient for the strategy's effectiveness.
Given the promising evidence—although still limited—additional studies should be conducted to identify specific strategies with phytochemical-rich food and beverage to mitigate muscle symptoms associated with EEIMD, as well as to elucidate potential mechanisms of action of these bioactive compounds. This knowledge may help professionals in dietary planning for athletes. Additionally, accurate critical analysis is recommended regarding methodological aspects that might interfere with the proper interpretation of supplementation effects, so that the understanding and practical application of the results can be solidly grounded.

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