Mitochondrial Dysfunction in Skeletal Muscle of a Fibromyalgia Model: The Potential Benefits of Melatonin

Abstract

Fibromyalgia syndrome (FMS) is considered a musculoskeletal disorder associated to other symptoms including chronic pain. Since the hypothesis of FMS etiogenesis is consistent with mitochondrial dysfunction and oxidative stress, we evaluated the pathophysiological correlation among these factors studying some proteins involved in the mitochondrial homeostasis. We focused our attention on the roles of peroxisome proliferator activated receptor gamma coactivator-1alpha (PGC-1α), mitofusin2 (Mfn2), and coenzyme Q10 (CoQ10) in reserpine-induced myalgic (RIM) rats that manifest fibromyalgia-like chronic pain symptoms. First, we underlined that RIM rats are a good model for studying the pathophysiology of FMS and moreover, we found that PGC-1α, Mfn2, and CoQ10 are involved in FMS. In fact, their expressions were reduced in gastrocnemius muscle determining an incorrect mitochondrial homeostasis. Today, none of the currently available drugs are fully effective against the symptoms of this disease and they, often, induce several adverse events; hence, many scientists have taken on the challenge of searching for non-pharmacological treatments. Another goal of this study was therefore the evaluation of the potential benefits of melatonin, an endogenous indoleamine having several functions including its potent capacity to induce antioxidant enzymes and to determine the protective or reparative mechanisms in the cells. We observed that melatonin supplementation significantly preserved all the studied parameters, counteracting oxidative stress in RIM rats and confirming that this indoleamine should be taken in consideration for improving health and/or counteract mitochondrial related diseases.

Keywords: fibromyalgia; melatonin; mitochondria; oxidative stress; skeletal muscle.

Figure 1

Spontaneous locomotor activity. The graph summarizes the distance travelled (A) and the speed (B) of spontaneous locomotor activity. * p ≤ 0.05 vs. RIM + H₂O; # p ≤ 0.05 vs. CTR; + p ≤ 0.05 vs. RIM + H₂O. CTR: control; H₂O: tap water; MEL: melatonin; RIM: reserpine-induced myalgia.

Figure 2

Myotube diameter and myogenin expression. The graph (A) shows the analyses of Feret’s myotube diameter of gastrocnemius skeletal muscle, expressed in µm. The immunofluorescence photomicrographs (B–E) show the gastrocnemius skeletal muscle myogenin expression of RIM rats (B), control rats (C), RIM rats plus tap water (D), and RIM rats supplemented with melatonin (E). Bar equal: 20 µm. Graph (F) summarizes the immunomorphometrical measurement of myogenin immunopositivity. * p ≤ 0.05 vs. RIM; # p ≤ 0.05 vs. CTR; + p ≤ 0.05 vs. RIM + H₂O. CTR: control; H2O: tap water; MEL: melatonin; RIM: reserpine-induced myalgia.

Figure 3

Gastrocnemius mitochondrial markers evaluation. Immunofluorescence photomicrographs of peroxisome proliferator activated receptor gamma coactivator-1alpha (A–D) and mitofusin2 (E–H) expression in gastrocnemius skeletal muscle of RIM rats (A,E), control rats (B,F), RIM rats plus tap water (C,G) and RIM rats supplemented with melatonin (D,H). Bar equal: 20 µm. The graphs summarize the immunomorphometrical measurement of peroxisome proliferator activated receptor gamma coactivator-1alpha (I) and mitofusin2 (J) immunopositivities. The graph (K) summarizes gastrocnemius coenzyme Q10 level of all experimental groups. * p ≤ 0.05 vs. RIM; # p ≤ 0.05 vs. CTR; + p ≤ 0.05 vs. RIM + H₂O. CoQ10: coenzyme Q10; CTR: control; H₂O: tap water; MEL: melatonin; Mfn2: mitofusin2; PGC-1α: peroxisome proliferator activated receptor gamma coactivator-1alpha; RIM: reserpine-induced myalgia.

Figure 4

Mitochondrial involvement in fibromyalgia syndrome. A schematic diagram representing the important role of mitochondria in normal and in FMS underlining the biosynthetic pathway mediated by PGC-1α. The decrease of PGC-1α expression induces downregulation of Mfn2 that, in turn, determined a decrease of CoQ10 expression in the inner of mitochondrial membrane. In mitochondria CoQ10 is a part of electron transport chain among several complexes likely to cytochrome C on the complex IV. It is also depicted the potential beneficial effects of melatonin in RIM rats and so, its role in the maintenance of health. Mfn2 = mitofusin2; PGC-1α = peroxisome proliferator-activated receptor gamma coactivator 1-alpha; ROS = reactive oxygen species; CoQ10 = coenzyme Q10; Cyt c = cytochrome complex; RIM rats = reserpine-induced myalgic rats; F0 = “Fraction 0” of the ATPase; it is a proton pore that is embedded in the mitochondrial membrane; F1 = “Fraction 1” of the ATPase; it is the portion responsible for hydrolyzing ATP; ADP = adenosine diphosphate; Pi= inorganic phosphate; ATP = adenosine triphosphate.