Pioglitazone improves skeletal muscle functions in reserpine-induced fibromyalgia rat model

Abstract

Background: Fibromyalgia (FM) is characterized by musculoskeletal pain, fatigue, sleep and memory disturbance. There is no definitive cure yet for FM-related health problems. Peroxisome proliferator-activated receptor's (PPAR's) activation is associated with insulin sensitisation and improved glucose metabolism. PPAR-c was reported to alleviate FM allodynia. Limited data are discussing its effect on motor disorders. Objective: To investigate the potential effect of PPAR-c agonists (pioglitazone, as one member of thiazolidinediones (TZD)) on motor dysfunction in reserpine-induced FM in a rat model. Materials and methods: Thirty-six male Wistar rats were divided into negative control (n ¼ 9) and reserpine-induced FM (n ¼ 27) groups. The latter was subdivided into three equal subgroups (n ¼ 9), positive control (untreated FM model), pioglitazone-treated and GW9662-treated. We evaluated muscle functions and activity of chloramphenicol acetyltransferase, superoxide dismutase, malondialdehyde, and serum levels of interleukin-8 and monocyte chemoattractant protein-1. Results: Pioglitazone significantly relieved fatigue, improved muscle performance, reduced inflammatory cytokines and enhanced antioxidant's activity, while GW9662, a known PPAR-c antagonist, aggravated the FM manifestations in the rat model. Conclusion: PPAR-c agonists show a promising role against FM-associated motor dysfunctions.

Rosiglitazone Ameliorates Cardiac and Skeletal Muscle Dysfunction by Correction of Energetics in Huntington’s Disease

“…Treating fibromyalgia (multisystem failure process involving the immune, musculoskeletal, and central nervous system ) in rats with PPAR-γ agonist, pioglitazone resulted in a significant improvement of skeletal muscle functions, reduced fatigability, and rapid recovery from fatigue [49], which is consistent with our results. Blocking the PPAR-γ pathway, though administration of GW9662, counteracted pioglitazone's protective effects [49]. Interestingly, experimental studies have also shown a reduction in the level of peroxisome proliferatoractivated receptor-gamma coactivator (PGC-1α), one of the proteins activated by PPAR-γ in skeletal muscles of HD mice models as well as HD patients [50].…”

“…Although PPAR-γ expression in skeletal muscle and the heart is relatively small, there are studies indicating that these receptors may play an important role in its metabolism and function [47,48]. Treating fibromyalgia (multisystem failure process involving the immune, musculoskeletal, and central nervous system ) in rats with PPAR-γ agonist, pioglitazone resulted in a significant improvement of skeletal muscle functions, reduced fatigability, and rapid recovery from fatigue [49], which is consistent with our results. Blocking the PPAR-γ pathway, though administration of GW9662, counteracted pioglitazone's protective effects [49].…”

Machine learning‐based phenotypic screening for postmitotic growth inducers uncover vitamin D3 metabolites as small molecule ribosome agonists

“…The top primary hit was calcitriol (1,25(OH)2D3) or the bioactive form of vitamin D3 (Figure 1E). Pioglitazone, one of the other primary hits, has been shown to be a PPARg agonist that significantly improved skeletal muscle functions in a reserpine‐induced fibromyalgia rat model 27 . Another primary hit, cholecalciferol, is an inactive precursor of calcitriol which requires sequential hydroxylation in the liver and then the kidney before it binds avidly to the vitamin D receptor, 28 and has also been shown to improve muscle strength and performance in athletes and old adults 29,30 .…”

“…Pioglitazone, one of the other primary hits, has been shown to be a PPARg agonist that significantly improved skeletal muscle functions in a reserpine-induced fibromyalgia rat model. 27 Another primary hit, cholecalciferol, is an inactive precursor of calcitriol which requires sequential hydroxylation in the liver and then the kidney before it binds avidly to the vitamin D receptor, 28 and has also been shown to improve muscle strength and performance in athletes and old adults. 29,30 The identification of pioglitazone and cholecalciferol as positive hits further supported the validity of our primary screening and data analysis, although the identification of both calcitriol and cholecalciferol despite their vastly different K d 's for VDR (3.8 pM and >20 mM, respectively) also suggested that VDRindependent mechanisms might be operating.…”

Pioglitazone Is a Mild Carrier-Dependent Uncoupler of Oxidative Phosphorylation and a Modulator of Mitochondrial Permeability Transition

“…The results of recent meta-analyses of population studies indicate that PIO efficiently decreases the blood pressure, the level of triglycerides, glycated hemoglobin, and blood glucose in fasting animals, as well as the risk of hypoglycemia [ 2 , 3 , 4 ]. Besides, due to its anti-inflammatory, antioxidant, and, perhaps, antibacterial and antifungal properties, PIO is now considered as a promising medicine for the treatment of a range of pathologic states, including Alzheimer’s disease [ 5 ], depressive disorder [ 6 ], non-alcoholic fatty liver disease [ 7 ], renal ischemia-reperfusion injury [ 8 ], Klebsiella pneumoniae infection [ 9 ], fibromyalgia-associated motor dysfunctions [ 10 ], respiratory infections (including Coronavirus disease 2019) [ 11 , 12 ], chronic obstructive pulmonary disease [ 13 ], cryptococcal meningitis [ 14 ], and ischemic outcomes induced by mild traumatic brain injury [ 15 ]. The intake of PIO is associated with a decrease in carotid intima-media thickness, a hallmark of atherosclerosis progression [ 2 , 16 ].…”