Low-level laser (light) therapy (LLLT) on muscle tissue: performance, fatigue and repair benefited by the power of light

2.2 Low-level laser therapy – Clinical trials: acute responses

The vast majority of papers involving LLLT and exercise in humans investigated the acute effects of this therapy on muscle performance in high-intensity exercises [25–31]. Only three studies have investigated the chronic effects of this therapy [32–34].

One of first published works was a clinical pilot study conducted by Gorgey et al. [26]. The authors applied the LLLT (808 nm) in pulsed mode (pulse repetition of 1–10,000 Hz) for 5 min (low energy) and 10 min (high energy) on the femoral quadriceps before muscle fatigue induction by neuromuscular electrical stimulation. The results showed that LLLT groups had a lower percentage of muscle fatigue compared to the control group, which had statistical significance. There was no significant difference between groups irradiated with LLLT.

Leal Junior et al. [27–29] and de Almeida et al. [25] investigated the effects of LLLT on the biceps brachii performance in double-blind placebo-controlled trial with very similar methodologies. Leal Junior et al. [27] investigated the effects of LLLT (655 nm) applied on the biceps brachii before Scott bench exercise. The exercise was performed with 75 % of the load corresponding to maximum voluntary contraction (MVC) until exhaustion. Five points were irradiated for 100 s on each point. The results showed a significant increase in number of repetitions of the LLLT group compared to placebo group. However, there was no increase in time of exercise and there was no decreasing in blood lactate levels.

With the same experimental design these authors used other LLLT (830 nm) applied on biceps brachii at four points [28]. The radiation time was 50 s at each point before starting exercise in Scott bench. The results were the same previously reported: LLLT group increased the number of repetitions compared to placebo.

De Almeida et al. [25] attempted to identify in a single study which wavelength would be better to increase the biceps brachii performance in high-intensity exercise. The LLLT (660 nm or 830 nm) was applied on biceps brachii at four points for 100 s on each point before starting the Scott bench exercise. The LLLT groups (660 nm or 830 nm) had a greater force and force peak compared to placebo. However, there was no significant difference between irradiated groups.

Another work reporting a double-blind placebo-controlled and randomized trial also involved biceps brachii fatigue [29]. This study investigated the effects of LLLT (cluster with 5 diodes of 810 nm) applied before Scott bench exercise with 75 % of MVC until exhaustion. Two points of the biceps brachii were irradiated for 30 s on each point. There were increases in number of repetitions and time of exercise, decreasing levels of lactate, CK and c-reactive protein after exercise.

Baroni et al. [30] investigated the effects of LLLT (cluster with 5 diodes of 810 nm) on energetic metabolism, muscle damage and delayed onset muscle soreness (DOMS) in young males after 5 sets of 15 eccentric contractions of the femoral quadriceps on the isokinetic dynamometer. There were 6 points of LLLT radiation on the femoral quadriceps during 30 s on each point. The LLLT applied before exercise promoted a smaller increase of lactate dehydrogenase (LDH) activity at 48 h after exercise, a smaller increase of CK in blood at 24 h and 48 h after exercise and less loss of MVC immediately and 24 h after exercise. However, the DOMS measured by visual analog scale (VAS) was equal to the LLLT and placebo groups.

De Marchi et al. [31] verified the effects of LLLT (cluster with 5 diodes of 810 nm) on fatigue, oxidative stress, muscle damage and human physical performance on treadmill. Six points of the femoral quadriceps were irradiated as performed by Baroni et al. [30], 4 points on the hamstrings and two points on gastrocnemius muscles were irradiated before progressive exercise performed on treadmill until exhaustion. The time of radiation was 30 s on each point. LLLT group increased absolute and relative maximal oxygen uptake as well as the time of exercise compared to placebo. The activities of LDH, muscle damage (CK) and lipid damage (thiobarbituric acid reactive substances, TBARS) were all significantly higher only in placebo group after exercise. The activity of SOD, an antioxidant enzyme, was also decreased only in the placebo group after exercise.

2.3 Low-level laser therapy – Clinical trials: chronic responses

Unlike previous researches, Ferraresi et al. [32] and Vieira et al. [33] verified the effects of LLLT on physical training programs in randomized and controlled clinical trials.

Ferraresi et al. [32] investigated the effects of LLLT (cluster with 6 diodes of 808 nm) on a physical training program with load corresponding to 80 % of one repetition maximum (1RM). The training program was performed twice a week for 12 weeks and LLLT was applied immediately after each workout. Seven regions of the femoral quadriceps were irradiated for 10 s per region. The LLLT group had a greater percentage gain of 1RM compared to the trained group without LLLT and the control group after training program. Only the LLLT group significantly increased the mean of peak torque and peak torque of knee extensor muscles in isokinetic dynamometry.

The second study was reported by Vieira et al. [33]. This study verified the effects of LLLT (cluster with 6 diodes of 808 nm) on a physical training program of low intensity (load relative to the anaerobic ventilatory threshold) on stationary bicycle. The physical training was conducted three times a week for 9 consecutive weeks. Five regions of the femoral quadriceps were irradiated with LLLT for 10 s per region. LLLT group was only group to decrease the fatigue index of the knee extensor muscles in isokinetic dynamometry.

Ferraresi et al. [34] conducted a study showing modulations in gene expression of human muscle by LLLT (cluster with 6 diodes of 808 nm). With the same experimental design and parameters of LLLT used in previous study [32], the authors investigated changes of the load at 1RM test and modulation of gene expressions in muscle tissue of the 10 young males allocated into two equal groups: LLLT and without LLLT. Biopsies from the vastus lateralis muscle were performed before and after the training program and analyzed by microarrays to identify modulation of gene expression throughout the whole human genome. Preliminary analysis identified that the LLLT group had more significant increase of load at 1RM test, the genes PPARGC1-α (mitochondrial biogenesis), mTOR (protein synthesis and muscle hypertrophy) and vascular endothelial growth factor (VEGF) (angiogenesis) were significantly upregulated only in the LLLT group compared to the non-LLLT control group. In addition, only in the LLLT group the genes MuRF1 (protein degradation and muscle atrophy) and IL-1β (inflammation) were downregulated [34].

2.4 Light-emitting diode therapy and exercise – Clinical trials: acute responses

Recently LEDT has begun to be investigated for the same previous purpose that LLLT was tested for; i.e., increased performance in human physical exercises [35–38]. LEDT are more accessible light sources and have a larger area compared to the light emitting laser diode.

Despite of the study conducted by Vinck et al. [35] does not have as primary objective an evaluation of muscle performance, this study was the first to report the effects of LEDT on delayed onset muscle soreness and human muscle performance in isokinetic dynamometer. These authors investigated the effects of LEDT (cluster with 32 LEDs of 950 nm) on DOMS after fatigue induction of the biceps brachii using an isokinetic dynamometer. The authors found no significant differences between groups LEDT and placebo for the peak torque and the level of pain measured by algometer and VAS.

Leal Junior et al. [36] compared the effects of a cluster with 69 LEDs (34 LEDs of 660 nm and 35 LEDs of 850 nm) with the single LLLT diode (810 nm) on the physical performance of volleyball players. Three tests of high intensity effort (Wingate test) were conducted on nonconsecutive days, during 30 s each test. The LEDT (cluster with 69 LEDs) or LLLT or placebo treatments were administered on two points on the belly of the rectus femoris muscle for 30 s of radiation on each point before starts the tests. LEDT group had a significant reduction of CK levels in blood after exercise compared to LLLT and placebo group. However, there was no increased performance and significant reduction of lactate levels in LEDT group compared to other groups.

Using the same LED cluster employed in his previous study [36], Leal Junior et al. [37] applied the LEDT for 30 s of radiation on a single point on the belly of biceps brachii muscle before exercise at 75 % MVC at Scott bench. The LEDT group increased the number of repetitions and time of contraction in the proposed exercise. Also reduced CK levels in blood, lactate and c-reactive protein (CRP) after exercise compared to placebo.

Baroni et al. [38] applied LEDT on three points of the femoral quadriceps muscle before starting a protocol of isokinetic dynamometry for induction of muscle fatigue. The radiation time was 30 s on each point. The results showed that the LEDT was effective to prevent the decrease in knee extensor peak torque.

Comparing the effects of LEDT with other modalities of treatment, Leal Junior et al. [39] tested the effects of cryotherapy and LEDT (cluster with 69 LEDs) on muscle recovery in a randomized double-blind placebo-controlled trial. Six athletes performed three Wingate tests on three different days. After each test, the athletes received placebo or LEDT or cryotherapy (5 min of body immersion in water at 5° C). The LEDT was applied on two points of the femoral quadriceps, two points on hamstrings and two points on gastrocnemius. The LEDT significantly decreased CK and lactate levels in blood but did not modulate CRP.

3.1 Energetic metabolism

3.2 Reactive oxygen species and reactive nitrogen species

Superoxide anion (O₂^•−) is the primary free radical ROS produced mainly by mitochondria and nicotinamide adenine dinucleotide phosphate (reduced form) (NADPH) oxidase in skeletal muscle [3, 49]. In the mitochondria O₂^•− is produced as a byproduct of oxidative phosphorylation and therefore its formation is always associated with mitochondrial activity, especially during physical exercise [1, 3, 49]. O₂^•− is produced mainly at complexes I and III of the ETC which release O₂^•− in the mitochondrial matrix and at the inter-membrane space, respectively. The production rate of O₂^•− is approximately 0.15 % of oxygen consumption in mitochondria together with the enzymatic activities of NADPH oxidase, xanthine oxidase and lipoxygenase that also produce O₂^•− [1, 3, 49]. Beyond O₂^•−, hydrogen peroxide (H₂ O₂) and hydroxyl radicals (OH^•) are also important ROS [1, 3, 49].

Nitric oxide (NO^•) is the primary nitrogen free radical. NO^• is synthesized from L-arginine amino acid by nitric oxide synthase (NOS). NO^• can be formed from the inorganic anions, nitrate (NO₃⁻) and nitrite (NO₂⁻) and can interact with superoxide anion (O₂^•−) to form peroxynitrite (ONOO⁻) [1, 3, 49]. In adult skeletal muscle there is expression of the three isoforms of NOS: neuronal (nNOS or type 1), inducible (iNOS or type 2) and endothelial (eNOS or type 3). However, the predominant isoform is nNOS [1, 3, 49].

ROS and RNS are produced by mitochondria, by NADPH oxidase activity in the sarcoplasmic reticulum and transverse tubules, and also by phospholipase A₂ and xanthine oxidase [49]. However, there are defenses against ROS and RNS activity in cells and tissues. These defenses are mainly the antioxidant activity of SOD, glutathione peroxidase (GPX) and catalase (CAT) [49]. There are three isoforms of SOD (SOD1 – 3) and five isoforms of GPX (GPX1 – 5), each with its specific location in the cell and extracellular places. For detailed information see the review by Powers and Jackson [49].

O₂^•− is rapidly broken down into H₂ O₂ by antioxidant enzymes (reaction 1) such as SOD-2. H₂ O₂ is broken down by catalase (reaction 2) and GPX with conversion of reduced glutathione (GSH) to oxidized glutathione (GSSG) (reaction 3) [1, 3, 49]. Moreover, H₂ O₂ can react with metals such as Fe²⁺ (reaction 4: Fenton reaction), which produces hydroxyl radicals (OH^• and OH⁻) which are extremely reactive [1, 3, 49]. Fe³⁺ is present in myoglobin, hemoglobin, CCO, and can be reduced to Fe²⁺ by superoxide radicals and then produce hydroxyl radicals (reaction 5: Haber – Weiss reaction). Hydroxyl radicals have a short half-life because they react with any organic molecules and can produce damage of proteins, DNA and lipids that are present in the cell membrane and therefore lead to tissue damage [1, 3, 49].

• Reaction 1: O₂^•− + O₂^•− + 2 H⁺ → H₂ O₂ + O₂
• Reaction 2: 2 H₂ O₂ → 2 H₂ O + O₂
• Reaction 3: 2 GSH + H₂ O₂ → GSSG + 2 H₂ O
• Reaction 4: (Fenton reaction): H₂ O₂ + Fe²⁺ → Fe³⁺ + OH^• + OH⁻
• Reaction 5: (Haber–Weiss reaction): O₂^•− + H₂ O₂ → OH^• + OH⁻ + O₂

During physical activity the contraction of skeletal muscle is the main source of ROS and RNS production and produces deleterious effects on muscle fibers, such as cellular and tissue damage, loss of contractile function and exercise performance [1, 3, 49, 50]. ROS and RNS can induce early onset of muscle fatigue in exercise through mechanisms involved in muscle contraction [1, 49] such as:

1. Decreased ATP synthesis: NO^• production in the mitochondria can reduce ATP synthesis by inhibition of CCO, muscle CK and glyceraldehyde-3-phosphate dehydrogenase (glycolytic pathway) thereby reducing ATP production [49].
2. Regulation of sarcoplasmic reticulum and Ca²⁺ release: ROS increases Ca²⁺ content in the sarcoplasm and promotes a slow Ca²⁺ reuptake [1, 49]. ROS also inhibits the activity of the ATPase enzyme of the Ca²⁺ pump in the sarcoplasmic reticulum (SERCA) leading to impairment of hydrolysis of ATP used for operating Ca²⁺ pump [1, 49]. NO^• also inhibits the activity of SERCA and results in decreased reuptake of Ca 5 from the sarcoplasm to the sarcoplasmic reticulum [49]. Prolonged exposure to ROS and RNS can induce a lasting release of Ca 5 through changes of the receptor sensitivity of channels for Ca 5 of the sarcoplasmic reticulum [3].
3. Contractile proteins: ROS and RNS can change the structure of contractile proteins; decrease the sensitivity of myofibrils to Ca²⁺; oxidize actin, myosin and troponin C impairing the formation of cross bridges, muscle contraction and production of muscle strength [1, 3, 49, 50].
4. Potential action: ROS seems to reduce the Na⁺-K⁺ pump activity, increase amounts of extracellular K⁺ that reduces the action potential for muscle fiber depolarization during exercise, contributing to the onset of early muscle fatigue [3].
5. ROS and RNS after muscle fatigue: ROS decreases the sensitivity of myofibrils to Ca²⁺ by accumulation of H₂ O₂ (via SOD-2) and/or OH^• (via Fenton reaction), impairing contractile function [3, 50]. High levels of O₂^•− can also inhibit the release of Ca²⁺ from sarcoplasmic reticulum and/or react with NO^• to produce ONOO⁻ which also affects Ca²⁺ release from the sarcoplasmic reticulum [3, 50]. Furthermore, NO^• can also bind to transition metals [49], such as Fe, and impair mitochondrial function [40, 51].
6. Muscle damage: the lipids that make up the muscle cell membrane (sarcolemma) are attacked by ROS and RNS during process of lipid peroxidation. Disruption of the sarcolemma promotes muscle cell death and all the contents are released into the extracellular environment, causing inflammation (degradation of cellular content), edema, pain and loss of contractile function [1, 49]. In this process, blood levels of muscle CK are increased, making it a useful parameter to measure muscle damage [52].

LLLT and LEDT have been used to combat ROS and RNS produced during physical exercise [20–22, 24, 25, 28–31, 36, 38, 39] for improvement in mitochondrial function that contributes to the reduction of muscle fatigue and the increase in muscle performance. LLLT and LEDT use CCO as the primary photoacceptor and the main effects of this interaction are increased ATP synthesis and increased mitochondrial function [24, 40–43, 51]. The relationship between light, mitochondria, ROS and RNS involves the reduction of ROS and the photodissociation of nitric oxide-cytochrome c oxidase (NO-CCO), contributing to the restoration of oxygen consumption and ATP synthesis in mitochondria [40–51].

NO-CCO photodissociation is based on the hypothesis that NO may compete with oxygen to bind to the iron-sulfur complex (complex I) and to centers of iron and copper (complex IV) in the respiratory chain and inhibit the mitochondrial ATP synthesis [40, 51] mainly in cells metabolically stressed [40], as occurs after muscle contraction [24]. However, the binding between NO-CCO can be broken by visible and NIR light energy [51, 53] restoring mitochondrial function to ATP synthesis [24, 40, 41, 43, 51]. Thus, the use of LLLT or LEDT after physical exercise may be more effective compared to its use before exercises.

It is known that physical exercise may decrease intracellular pH [1]. An accumulation of H⁺ can inactivate the Cu-Zn-SOD (SOD-1 and SOD-3) through of a protonation of the residue of histidine 61 (Hys61) in the active center of these enzymes [51]. However, LLLT can reverse this process and re-activate SOD-1 and SOD-3 [51] (Figure 3).

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Figure 3

Based on reference [51]: Deprotonation of histidine and formation of the N-Zn bond to restore the active center structure and activity of the superoxide dismutase enzyme (SOD) by LLLT or LEDT.

De Marchi et al. [31] reported that SOD activity did not change even after intense exercise in LLLT group, thereby increasing physical performance compared to placebo-LLLT group that had decreased SOD activity and had the worst performance. Liu et al. [21] found increases of 44 % and 58 % in SOD activity after 24 h and 48 h after eccentric exercise and irradiation with LLLT.

Possibly LLLT and LEDT improves mitochondrial function, dismutation of O₂^•− via SOD and decreases formation of ONOO⁻ [51]. In addition, LLLT can reduce H₂ O₂ via CAT and GPX and can reduce the formation of hydroxyl radicals which contribute to the lower damage of the muscle cell membrane, as evidenced by lower lipid peroxidation and lower blood levels of muscle CK reported in previous studies [21, 31]. Also, the activation of calpain and caspase mediated by ROS [49] can be inhibited by LLLT and LEDT, since these therapies can modulate oxidative stress [31, 51]. Figures 4 and ​and55 illustrate the action of LLLT and LEDT on antioxidant enzymes and ROS and RNS in muscle contraction, respectively.

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Figure 4

Based on reference [1]. Effects of LLLT or LEDT on reactive oxygen species (ROS) and reactive nitric species (RNS) production and antioxidant enzymes.

⊗: decreased or inhibited production.

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Figure 5

Based on references [1, 32, 40, 49]. Effects of LLLT or LEDT on reactive oxygen species (ROS), reactive nitric species (RNS), mitochondria and muscle contraction. SERCA = sarcoplasmatic reticulum Ca²⁺ pump. Dashed line: inhibited activity and ⊗: decreased or inhibited function.

However, beside increased mitochondrial function and activity of antioxidant enzymes such as SOD, CAT and GPX, other mechanisms of action of LLLT and LEDT may be involved in reduction of muscle fatigue and increase of muscle performance [20–22, 24, 25, 28–33, 36, 38, 39]; these may be: (i) improvement in the sensitivity of myofibrils and Ca²⁺ channels to the Ca²⁺ ion, (ii) increase in Ca²⁺ uptake from sarcoplasm to sarcoplasmic reticulum via Ca²⁺ pump (ATP dependent), (iii) improvement in the formation of cross-bridges and production of contractile force, (iv) increase in the activity of Na⁺-K⁺ pump (ATP-dependent) to reduce the excess of extracellular K⁺ and ensure the depolarization of muscle fibers to continue the exercise, and (v) lower muscle damage and leakage of muscle contents into the blood, such as muscle CK and myoglobin.

3.3 Repair of muscle damage

Muscle damage is a disruption in the myofibrils which is a process accompanied by inflammation at the site of injury and contractile function losses [54]. The regeneration of muscle tissue after different injurious is a process that usually occurs in six phases taking 21 days overall [54]:

• Phase 1 (2 days after injury): necrosis of injured tissue muscle, acute inflammation with swelling, increased collagen deposition, increased connective tissue and scarring formation;
• Phase 2 (3 days): satellite cell activation;
• Phase 3 (5 days): fusion of myoblasts at the site of injury and increased density of connective tissue;
• Phase 4 (7 days): regenerating muscle cells extending outside of the former cylinders of the basal lamina to the injured site and then invading the scar tissue;
• Phase 5 (14 days): the scar in the injured site reduces in size and new myofibrils fill the gap at the injured site;
• Phase 6 (21 days): interweaving and fusion of the ends of myofibrils and with further reduction in connective and scar tissue.

The regeneration of muscle tissue is limited, but does allow activation, proliferation and differentiation of muscle satellite cells into new myonuclei and/or myofibrils [54–57]. Satellite cells are located at the basal layer of myofibrils and may be quiescent, proliferating or differentiating according to the harmful stimuli [55–57]. These cells are considered reserve cells, because although they are not stem cells such as in embryonic development, these cells are able to renew the myogenesis program in response to a muscle injury [58], such as micro-lesions from strength training or high intensity exercises [55–57, 59–61].

Muscle injuries promote inflammation and higher concentrations of neutrophils and macrophages at the site of injury that produce chemoattractants to attract the satellites cells to the region [56, 57]. Satellite cells are activated, proliferate and differentiate by molecular pathways such as modulation of gene expression related to quiescence (Pax7, c-Met, Myf5), proliferation/activation (MyoD1, Myf5, M-cadherin) and differentiation (desmin, MRF4 and myogenin) [56, 57].

Satellite cells that have already differentiated can be fused to the damaged muscle fibers as new myonuclei, providing gene expression that encodes new contractile proteins or improve the myonuclear domain [62–64]. In addition, these cells can be activated and form new myoblasts that fuse to form myotubes which will produce new myofibrils [56, 57].

Once the importance of satellite cells in the process of muscle repair became known, some authors investigated the effects of LLLT on these cells [65–68]. Studies in experimental models have shown that LLLT increases the formation of new myofibrils that fill the gap in muscle injury and contractile characteristics can return to the site of injury [65, 66]. Bibikova and Oron [67] observed that LLLT (632.8 nm) promoted a greater maturation of young myofibrils compared to those not irradiated. Shefer et al. [68] found an increase of the number and activation of satellite cells around the myofibrils irradiated with LLLT (632.8). Shefer et al. [68] also observed that LLLT (632.8) was effective in increasing levels of B-cell lymphoma 2, an antiapoptotic protein related to cell viability, and decreasing BAX, a pro-apoptotic protein. Nakano et al. [69] reported that LLLT (830 nm) increased satellite cells by 5-Bromo-2′-deoxyuridine (BrdU) incorporation, angiogenesis and maintained the diameter of rat myofibrils submitted to process of muscle atrophy.

Currently there is no study that investigated LLLT or LEDT and satellite cell activity in humans. Only in vitro studies and experimental models are reported in scientific literature, which show a positive influence of LLLT on the cell cycle, proliferation and activation of these cells [66, 68, 70, 71].

In addition to satellite cells, the control of inflammation, proteolysis, ROS and RNS, synthesis and remodeling of collagen and ATP levels are fundamental to the success of muscle damage repair [21, 43, 72–78]. Studies in experimental models have shown that LLLT can modulate amounts of collagen at the site of injury [72, 73, 78]; inhibit inflammation by lower expression of tumor necrosis factor (TNF)-alpha (TNF-α) and COX-2 [21, 74, 77]; decrease ROS by smaller lipid peroxidation (TBARS and lower levels of MDA) [21, 72, 73, 76], reduce RNS by inhibiting synthesis of iNOS [72], decrease the expression of nuclear factor kappa B (NF-κβ) and CK (related to proteolysis) [21, 72, 73]; increase activity of SOD [21, 76], increase the expression of VEGF receptor (VEGFR-1) in the capillaries and in satellite cells [75] and increase activity of respiratory chain for ATP synthesis and repair muscle damage [43].

3.4 Gene expression effects

Several studies report specific molecular pathway signaling for each type of physical training, where the expression and/or suppression of specific genes are essential for better physical performance [10, 11, 79–83].

Strength training or high-intensity exercise have well defined signaling pathways which involve specific genes related to muscle satellite cells at the quiescent state (c-Met genes, Myf5 and Pax7), activated (genes MyoD1, Myf5, M-cadherin) and differentiation to form new myonuclei and/or myofibrils (genes desmin, myogenin and MRF4) in response to micro-lesions [55–57, 59–61]. Also, strength training or high intensity exercise are influenced by genes related to protein synthesis (muscle hypertrophy) as IGF-1, AKT, mTOR and p70 ^S6K [10, 81]; genes regulating protein degradation (atrophy) as TNF-α, FOXO, FBXO32, TRIM63 or MuRF1, MSTN, E3 ubiquitin ligases and enzymes involved in proteolytic process by ubiquitin-proteasome system [10, 11, 81, 82, 84].

Gene expression changes related to endurance training or low intensity exercises include mitochondrial biogenesis involving upregulation of CCO, nuclear respiratory factor (NRF) 1 and 2, transcription factor A mitochondrial (TFAM) and peroxisome proliferator-activated receptor gamma coactivator 1 α (PPARGC-1α), all related to mitochondrial biogenesis [10, 11, 81, 82, 84]. When PPARGC-1α is upregulated there is an indication of mitochondrial biogenesis and more fatty acids oxidation in the muscles, also relating to the transition between the fiber types as type II to type I, which has greater oxidative potential [10, 79, 80]. This transition provides biomechanical adaptations such as resistance to fatigue in strenuous exercise at low to medium intensity [10, 79, 80].

The identification of the molecular mechanisms modulated by LLLT and LEDT can aid the understanding of the effects of these therapies on the gene expression changes related to different types of exercises [10, 11, 83] as previously suggested [32, 33]. However, the literature has a lack of studies involving gene expression in humans, because it involves invasive procedures like muscle biopsy [83].

With this perspective in mind, Ferraresi et al. [34] investigated the effects of LLLT (cluster with six diodes of 808 nm) on the physical performance of 10 young males undergoing physical strength training. Preliminary results showed that the LLLT group had upregulated the genes PPARGC1-α (mitochondrial biogenesis), mTOR (protein synthesis and muscle hypertrophy) and VEGF (angiogenesis). Furthermore, only the LLLT group downregulated MuRF1 (protein degradation and muscle atrophy) and IL-1 β (inflammation) (Figure 6).

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Figure 6

Based on references [10, 11, 84]. Mitochondrial biogenesis, protein synthesis and protein breakdown signaling modulated by LLLT associated to exercise. Gray boxes were upregulated by LLLT and black boxes were downregulated by LLLT.

CF and NAP were funded by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). MRH was supported by USNIH grant RO1AI050875.