Combined methylphenidate and fluoxetine treatment in adolescent rats significantly impairs weight gain with minimal effects on skeletal development

Chirokikh, Alexander A.; Uddin, Sardar M Z; Areikat, Nadine; Jones, Rachel; Duque, Edie; Connor, Carly; Hadjiargyrou, Michael; Thanos, Panayotis K.; Komatsu, David E.

doi:10.1016/j.bone.2022.116637

Cited by 7 publications

(9 citation statements)

References 52 publications

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“…Thus, the weight difference between the WT and KO mice could possibly serve as a confounding factor in this configuration due to the gravitational pull acting on the mice as they grasped the grip bar, especially as body weight is known to be a confounding variable in grip strength tests 54 . Lastly, previous muscle and bone studies also normalized by weight and in some cases significant differences no longer remained 55,56 …”

Section: Discussionmentioning

confidence: 99%

“…54 Lastly, previous muscle and bone studies also normalized by weight and in some cases significant differences no longer remained. 55,56 We also postulated that changes in skeletal muscle, stemming from Mustn1 ablation, might potentially lead to observable alterations of limb loading dynamics. Among the three planes of force, only the vertical force exhibited a significant difference at 4 months of age, demonstrating a specific influence of Mustn1 ablation on this force vector.…”

Section: Building Upon Previous In Vivo and In Vitro Data On Mustn1mentioning

confidence: 99%

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Mustn1 ablation in skeletal muscle results in functional alterations

Kim,

Singh,

Kaczmarek

et al. 2023

FASEB BioAdvances

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Mustn1, a gene expressed exclusively in the musculoskeletal system, was shown in previous in vitro studies to be a key regulator of myogenic differentiation and myofusion. Other studies also showed Mustn1 expression associated with skeletal muscle development and hypertrophy. However, its specific role in skeletal muscle function remains unclear. This study sought to investigate the effects of Mustn1 in a conditional knockout (KO) mouse model in Pax7 positive skeletal muscle satellite cells. Specifically, we investigated the potential effects of Mustn1 on myogenic gene expression, grip strength, alterations in gait, ex vivo investigations of isolated skeletal muscle isometric contractions, and potential changes in the composition of muscle fiber types. Results indicate that Mustn1 KO mice did not present any substantial phenotypic changes or significant variations in genes related to myogenic differentiation and fusion. However, an approximately 10% decrease in overall grip strength was observed in the 2‐month‐old KO mice in comparison to the control wild type (WT), but this decrease was not significant when normalized by weight. KO mice also generated approximately 8% higher vertical force than WT at 4 months in the hindlimb. Ex vivo experiments revealed decreases in about 20 to 50% in skeletal muscle contractions and about 10%–20% fatigue in soleus of both 2‐ and 4‐month‐old KO mice, respectively. Lastly, immunofluorescent analyses showed a persistent increase of Type IIb fibers up to 15‐fold in the KO mice while Type I fibers decreased about 20% and 30% at both 2 and 4 months, respectively. These findings suggest a potential adaptive or compensatory mechanism following Mustn1 loss, as well as hinting at an association between Mustn1 and muscle fiber typing. Collectively, Mustn1's complex roles in skeletal muscle physiology requires further research, particularly in terms of understanding the potential role of Mustn1 in muscle repair and regeneration, as well as with influence of exercise. Collectively, these will offer valuable insights into Mustn1's key biological functions and regulatory pathways.

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Section: Discussionmentioning

confidence: 99%

Section: Building Upon Previous In Vivo and In Vitro Data On Mustn1mentioning

confidence: 99%

Mustn1 ablation in skeletal muscle results in functional alterations

Kim,

Singh,

Kaczmarek

et al. 2023

FASEB BioAdvances

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“…6 Animal experiments have also shown that MP inhibits weight gain, especially at high doses. 11,14,18 Even when the pair-feeding paradigm was applied in one study, weight gain decreased in the high-dose MP group. 11 Similarly, the results of the current study showed that MP significantly inhibited weight gain in rats in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

Effects of methylphenidate on femoral bone growth in male rats

Say,

Önger,

Say

et al. 2023

Hum Exp Toxicol

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The use of Methylphenidate (MP) can have adverse effects on bone growth and mineralization. This study aimed to investigate the underlying pathophysiology of MP-induced skeletal deficits in growing rats using stereological and immunohistochemical methods. Male rats, aged 4 weeks, were orally treated with MP through an 8-h/day water drinking protocol. The rats ( n=30) were randomly divided into three groups: MP-High Dose (30/60 mg/kg/day MP), MP-Low Dose (4/10 mg/kg/day MP), and control (water only). After 13 weeks, the femoral bones were assessed using calliper measurements, dual-energy X-ray absorptiometry, and biomechanical evaluation. The total femur volume, cartilage volume, growth zone volume, and volume fractions were determined using the Cavalieri method. Immunohistochemical analyses were conducted using alkaline phosphatase and anti-calpain antibody staining. Rats exposed to MP exhibited significant reductions in weight gain, femoral growth, bone mineralization, and biomechanical integrity compared to the control group. The total femoral volume of MP-treated rats was significantly lower than that of the control group. The MP-High Dose group showed significantly higher ratios of total cartilage volume/total femoral volume and total growth zone volume/total femoral volume than the other groups. Immunohistochemical evaluation of the growth plate revealed reduced osteoblastic activity and decreased intracellular calcium deposition with chronic MP exposure. The possible mechanism of MP-induced skeletal growth retardation may involve the inhibition of intracellular calcium deposition in chondrocytes of the hypertrophic zone in the growth plate. In this way, MP may hinder the differentiation of cartilage tissue from bone tissue, resulting in reduced bone growth and mineralization.

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“…The mechanism by which MPH exerts this effect on growth is not known, although the most widely accepted hypothesis is that it is due to its anorexigenic effect [ 11 , 12 ]. However, MPH has been demonstrated to impair weight gain independently of food intake in rats [ 13 , 14 ]. Therefore, a deleterious effect on chondrocytes cannot be discarded [ 15 ].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, few studies have evaluated the toxicity of MPH in vitro [ 15 , 23 ], and the only study on chondrocytes so far tested much higher concentrations of MPH than plasmatic ones [ 15 , 24 ]. For all these reasons, and given that in vivo studies would be influenced by MPH metabolic effects [ 13 , 14 ], we focused on investigating the effects of clinically relevant concentrations of MPH on chondrocyte viability and maturation in an in vitro growth plate model. Our results indicate that even though MPH did not alter chondrocyte viability, it produced changes in the expression of genes related to their differentiation process.…”

Section: Introductionmentioning

confidence: 99%

Methylphenidate Promotes Premature Growth Plate Closure: In Vitro Evidence

Pazos-Pérez

Piñeiro-Ramil

Franco-Trepat

et al. 2023

IJMS

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It is well known that patients with attention deficit hyperactivity disorder treated with stimulants, such as methylphenidate hydrochloride (MPH), have reduced height and weight. Even though MPH has an anorexigenic effect, an additional impact of this drug on the growth plate cannot be discarded. In this study, we aimed to determine the cellular effect of MPH on an in vitro growth plate model. We tested the effects of MPH on the viability and proliferation of a prechondrogenic cell line via an MTT assay. In vitro differentiation of this cell line was performed, and cell differentiation was evaluated through the expression of cartilage- and bone-related genes as measured via RT-PCR. MPH did not alter the viability or proliferation of prechondrogenic cells. However, it reduced the expression of cartilage extracellular matrix-related genes (type II collagen and aggrecan) and increased the expression of genes involved in growth plate calcification (Runx2, type I collagen, and osteocalcin) at different phases of their differentiation process. Our results evidence that MPH upregulates genes associated with growth plate hypertrophic differentiation. This may induce premature closure of the growth plate, which would contribute to the growth retardation that has been described to be induced by this drug.

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Combined methylphenidate and fluoxetine treatment in adolescent rats significantly impairs weight gain with minimal effects on skeletal development

Cited by 7 publications

References 52 publications

Mustn1 ablation in skeletal muscle results in functional alterations

Mustn1 ablation in skeletal muscle results in functional alterations

Effects of methylphenidate on femoral bone growth in male rats

Methylphenidate Promotes Premature Growth Plate Closure: In Vitro Evidence

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