Skip to main content
NCBI home page
Wiley Open Access Collection logoLink to Wiley Open Access Collection
. 2025 Feb 13;604(6):2512–2524. doi: 10.1113/JP287765

Early sensorimotor restriction in rats induces age‐dependent mitochondrial alterations in skeletal muscles and brain structures

Mélanie Van Gaever 1, Olivier Dupuy 2,3, Erwan Dupont 1, Marie‐Hélène Canu 1, Frederic Daussin 1,✉
PMCID: PMC12997013  PMID: 39945506

Abstract

Abstract

A sedentary lifestyle can lead to motor and cognitive deficits, increasing the risk of neurodegenerative diseases in ageing. Emerging hypotheses suggest that these functional alterations may be related to energy metabolism. Indeed, ATP produced by mitochondria is essential for muscle contraction, neurotransmission and brain plasticity processes. Although a sedentary lifestyle has been associated with mitochondrial alterations in skeletal muscle, the potential effects on brain structures have yet to be investigated. The present study aimed to determine whether early sensorimotor restriction (SMR) alters mitochondrial metabolism in rat muscles and brain structures. Enzyme activities of citrate synthase (CS) and respiratory chain complexes I, II and IV were measured using a spectrophotometric technique and mitochondrial respiration was assessed using high‐resolution respirometry in two hind limb muscles [soleus and extensor digitorum longus (EDL)] and four brain structures (sensorimotor cortex, striatum, prefrontal cortex and hippocampus) in control rats and rats experiencing early SMR from birth to day 28. Mitochondrial enzyme activities decreased in the soleus (complexes I and II), in the EDL (complex I) and in the hippocampus (complexes I and IV) in an age‐dependent manner, whereas no effect was observed in other brain structures. CS activity decreases in the soleus and increases transiently in the striatum and sensorimotor cortex at postnatal day 15. Mitochondrial respiration was reduced in the soleus and in the sensorimotor cortex (CI and CI+CII). Early SMR appears to induce quantitative and qualitative mitochondrial alterations in skeletal muscles and certain brain structures involved in cognitive and motor processes.

graphic file with name TJP-604-2512-g006.jpg

Key points

  • Early sensorimotor restriction (SMR) alters mitochondrial enzyme activities and mitochondrial respiration in skeletal muscles and brain.

  • Mitochondrial alterations induced by early SMR are age‐dependent, structure‐dependent and complex‐dependent.

  • Mitochondrial enzyme activities increase during development and the evolution pattern is specific to the different structures.

Keywords: brain, childhood, immobilization, mitochondria, muscle

Abstract figure legend This study aimed to determine whether early sensorimotor restriction (SMR) alters mitochondrial enzyme activities in rat muscles and brain structures. SMR was induced via immobilizing the hind limbs of pups for 16 h per day during the dark phase from birth to postnatal day (PND) 28. Enzyme activities of citrate synthase (CS) and respiratory chain complexes I, II and IV were measured at two developmental stages (PND15 and PND28), using a spectrophotometric technique, in two hind limb muscles [soleus and extensor digitorum longus (EDL)] and four brain structures (sensorimotor cortex, striatum, prefrontal cortex and hippocampus) in control and SMR rats. Mitochondrial respiration was assessed at PND28 in muscles and brain structures (sensorimotor cortex, prefrontal cortex and hippocampus). Our results show that CS activity was transiently decreased in the slow‐twitch soleus and increased in the sensorimotor cortex and striatum, conmprisng two brain structures involved in motor functions. Complex activities were decreased in EDL at PND15 only, in the soleus at both stages and in the hippocampus at PND28 only. The mitochondrial respiration driven by complex I or complexes I+II was reduced in the soleus and sensorimotor cortex. Mitochondrial enzyme activities are therefore sensitive to early SMR in skeletal muscles and brain structures involved in cognitive and motor processes.

graphic file with name TJP-604-2512-g006.jpg

Introduction

Childhood is a period of the construction of the organism, and it is now well established that physical activity and interaction with the environment are necessary for a typical and harmonious maturation of the organism, especially for the central nervous system (Luhmann, 2021). In a recent report, the World Health Organization (WHO, 2022) stated that the lack of physical activity could increase the prevalence of chronic diseases to 500 million people by 2030. Today, more than 25% of the world's population is affected by sedentary behaviour. In particular, time spent sitting is associated with a higher mortality rate (Stamatakis et al., 2019). This increasingly sedentary lifestyle partly explains the decline in the fitness levels observed for many years in the adult and child populations (Lamoureux et al., 2019; Olds et al., 2006; Tomkinson, 2007). In addition, everyday accidents or illnesses that temporarily reduce physical activity can be detrimental, especially during children's development. In addition to the impact of insufficient physical activity on the health of the population, particularly in children, one of the major consequences will be the financial cost to public and health policies.

In recent years, the hypothesis that cerebral metabolism is involved in cognitive decline has emerged, and precisely the implication of the role of cerebral mitochondria has been pointed out to protect the brain against ageing and neurodegenerative disease (Bernardo et al., 2016). At rest, the brain consumes ∼20% of the body's total oxygen, and neurons are highly dependent on mitochondrial energy production because of their limited glycolytic capacity (Magistretti & Allaman, 2015). This energy is essential to support various cellular processes, such as the synthesis and recycling of neurotransmitters and the maintenance of neuronal membrane potential. Furthermore, mitochondria also play a crucial role in cell survival and death‐related mechanisms by maintaining cellular redox potential, regulating apoptotic pathways and contributing to the regulation of synaptic plasticity (Hollville et al., 2019). Considering the importance of mitochondrial involvement in brain function, several studies found it that it was not unexpected that mitochondrial dysfunction explained the cognitive ageing process (Bartman et al., 2024; Reutzel et al., 2020). It has been recognized as an early event in Alzheimer's pathology, preceding and inducing neurodegeneration and memory loss (Bernardo et al., 2016; O'Reilly et al., 2023).

Mitochondrial brain plasticity appears to occur following a physical exercise program (Burtscher et al., 2021, 2022; Marques‐Aleixo et al., 2012; O'Reilly et al., 2023). Indeed, Dietrich et al. (2008) reported that mitochondrial density and respiration increased in the hippocampus of adult male and female mice after 4 weeks of free wheel running. However, the relationship between cerebral mitochondrial plasticity and physical activity is still unclear and remains an important research question (Burtscher et al., 2021). In particular, the relationship between a lack of physical activity or a sedentary lifestyle and mitochondrial function during development remains to be elucidated.

Therefore, the present study is the first to compare the effects of postnatal sensorimotor restriction (SMR) by partial immobilization from birth to postnatal day (PND) 28 on mitochondrial metabolism in rat muscle and brain. Enzymatic activities of citrate synthase (CS) and complexes I, II and IV of the oxidative chain were measured in two hindlimb muscles and in brain structures involved in motor or cognitive functions. The analysis was performed at two developmental stages (PND15 and PND28) and in both sexes. Mitochondrial respiration was measured in muscles and brain structures at PND28. Because mitochondria appear to be sensitive to physical activity, we hypothesize that partial immobilization may lead to an alteration of mitochondrial electron transport chain (ETC) enzyme activities in both muscle and brain.

Methods

Animals and diet

Sprague–Dawley rats were supplied from Charles River Laboratories (L'Arbresle, France). Rats were housed in standard cages to maintain a social environment (typical cage) in a room under a 12:12 h light/dark photocycle at 22 ± 2°C, and with ad libitum access to water and food. After 1 week of acclimatization, one male and one female were put in the same cage. After mating, pregnant females were transferred into individual cages. At birth (PND1), each litter was normalized to 10 pups with an equivalent number of males and females when possible and assigned to one of the experimental groups: control (CTRL) or SMR. The body weight of pups was assessed daily from PND1 to PND28. Measurements were conducted at two distinct time points: PND15, representing the equivalent of a young child in human, and PND28, corresponding to adolescence (Semple et al., 2013; Zeiss, 2021). Twelve litters of pups were used in this study: four control (n = 20) and four SMR (n = 20) at PND15 and two control (n = 20) and two SMR (n = 19) at PND28. All manipulations were carried out following the European Communities Council Directive 2010/63/EU and approved by the Regional Committee on Ethics in Animal Experiments (CEEA75, APAFIS#2021‐020818231865).

SMR

To cause early SMR, the hind limbs of pups were immobilized for 16 h per day during the dark phase every day from birth to PND28 (Delcour et al., 2018). Animals were free to move 8 h per day during the light phase. For newborns weighing less than 10 g, the hind limbs were immobilized with medical tape applied around the feet and the ankle. Beyond 10 g, hind limbs were immobilized in an extended position and taped to a cast adapted to the animal's size and by a belt at the abdominal level as previously described (Delcour et al., 2018). This cast made it possible to immobilize the entire hindquarters of the animal. This procedure was well tolerated by animals and allowed them to move, urinate, defecate, suck and receive maternal care, similar to control pups. Daily checks were carried out to ensure the animals’ good health. For the immobilization and cast removal procedures, pups were separated from their mother for a maximum of 15 min, twice a day. Control rats received comparable daily handling to minimize the possible impact of stress induced by the manipulation and maternal separation.

Tissue collection

Tissue sampling was performed at PND15 and PND28 from 30 min to 2 h after cast removal. After anaesthesia with isoflurane (3% induction in 1.4 L min−1 air), the animals received a lethal i.p. injection of T‐61 (i.e. embutramide, mebezonium iodide and tetracaine hydrochloride) (0.3 mL kg−1 body weight). An intracardiac infusion of 0.9% NaCl at 4°C was performed until complete exsanguination. Then, a craniotomy was performed to expose the cerebral cortex. The dura mater was resected. Samples of the following structures were removed: sensorimotor cortex corresponding to the hind limb somatotopic area, prefrontal cortex, striatum and hippocampus. EDL and SOL muscles were also removed and weighed. All samples were frozen in liquid nitrogen and stored at −80°C for further analysis of enzyme activities.

Enzyme activities

Brain tissues were homogenized manually in a potter in homogenization buffer (120 mm KCl, 20 mm Hepes, 2 mm MgCl2, 1 mm EGTA and 5 mg mL−1 bovine serum albumin, pH 47.4) followed by the addition of hypotonic buffer (25 mm potassium phosphate and 5 mm MgCl2, pH 7.2). The samples were then submitted to three steps of a freeze–thaw cycle in liquid nitrogen. The samples were centrifuged at 3000  g for 10 min at 4°C, and the supernatant was kept on ice until the analysis. Pulverized frozen skeletal tissues were homogenized with a vibrating microbead homogenizer in the same homogenization buffer and added the same hypotonic buffer. The samples were then submitted to liquid nitrogen for three rounds of the freeze‐thaw cycle. The samples were centrifuged at 600  g for 10 min at 4°C, and the supernatant was kept on ice until the analysis. The protein content was determined in the supernatant in triplicate using a Bradford Assay Kit (DC Protein Assay; Bio‐Rad, Hercules, CA, USA). Tissue protein concentrations were adjusted for each enzyme activity to obtain stable measurements over at least 10 min.

The activity of CS was determined spectrophotometrically at 412 nm following the reduction of 2 mm 5,5′‐dithio‐bis(2‐nitrobenzoic acid) (i.e. DTNB) in the presence of 0.1 mm acetyl‐CoA and 12 mm oxaloacetic acid in 200 mm Tris buffer (pH 7.4). The rotenone‐sensitive NADH‐decyl ubiquinone oxidoreductase (complex I) assay was performed at 340 nm using the acceptor 2,3‐dimethoxy‐5‐methyl‐6‐n‐decyl‐1,4‐benzoquinone (i.e. DB) (80 µm) and NADH as electron donor (200 µm) in 10 mm Tris buffer (pH 8.0). The addition of 4 µm of rotenone was used to quantify the rotenone‐sensitive activity. Cytochrome c oxidase activity (complex IV) was determined at 550 nm using 10 µm reduced cytochrome c as a donor and 2.5 mm n‐dodecyl‐ß‐maltoside to permeabilize both mitochondrial membranes in 100 mm potassium phosphate buffer (pH 7.0).

All of the enzyme assays were determined in duplicate. For the comparison of CTRL and SMR groups, the results were normalized to the control group, which was set to 1. To determine the evolution of mitochondrial enzyme activities from PND15 to PND28, the results of PND28 were normalized to PND15, which was set to 1.

Mitochondrial respiration

SOL and EDL muscle fibres were manually separated in a cold BIOPS solution and permeabilized using 50 µg L−1 of saponin in BIOPS with gentle agitation at 4°C for 30 min. Then, the muscle fibres were rinsed twice in the mitochondrial respiration medium Mir05 and weighed on a precision balance. Finally, 2–4 mg of fibres were placed in a chamber containing 2 mL of oxygenated Mir05 to assess mitochondrial respiration.

Brain tissues were homogenized manually in a potter in the Mir05 solution. Next, 20 µL of homogenate, corresponding to 2 mg of tissue, was placed in chamber containing 2 mL of oxygenated Mir05 to measure mitochondrial respiration. Saponin (30 µg mL−1) was injected in the chamber before the addition of mitochondrial substrates to permeabilize cells.

The oxygen consumption (JO2) of the muscle fibres and brain homogenates was assessed at 25°C utilizing O2k sensors and recording with DatLab, version 7.4  (Oroboros Instruments, Innsbruck, Austria). Mitochondrial substrates and inhibitors were successively introduced after achieving a steady state. The protocol started with the injection of pyruvate (5 mm), malate (2 mm) and glutamate (10 mm) without ADP assessed the JO2 of the ETC uncoupled from ATP synthase. The injection of ADP (5 mm) evaluated the JO2 of the ETC coupled with ATP synthase (OXPHOS state) and was primarily driven by complex I (CI). The addition of succinate (10 mm, a complex II substrate) evaluated the JO2 of the ETC driven by complexes I and II (CI+II). Inhibiting complex I with rotenone (0.5 µm) assessed the OXPHOS JO2 driven by complex II. Final additions of N,N,N′,N′‐tetramethyl‐p‐phenylenediamine dihydrochloride (i.e. TMPD) (0.5 mm) and ascorbate (2 mm) allow measurement of JO2 driven by complex IV.

Statistical analysis

Data are reported as the mean ± SD and n represents the number of animals used. Data normality was assessed by Kolmogorov–Smirnov test. A two‐way ANOVA was performed for parametric samples, with Tukey's multiple comparisons as a post hoc test. For non‐parametric samples, the Mann–Whitney test was applied. In both cases, tests were used to measure sex and group effects. As very few significant differences between sexes were observed in all the parameters, males and females were pooled to investigate the effect of SMR alone. For parametric samples, a t test was applied. For non‐parametric samples, a Mann–Whitney was applied. Data were analysed using Prism, version 9.4.1 (GraphPad Software Inc., San Diego, CA, USA). P < 0.05 was considered statistically significant.

Results

Impact of SMR on body weight and hindlimb muscle weight

At birth (PND1), the body weight was similar in both groups (CTRL: 6.48 ± 0.36 g; SMR: 6.47 ± 0.57 g, P = 0.9250, n = 40 for each group). During development, SMR rats gained significantly less weight than CTRL rats. Body weight was lower in SMR rats than in CTRL rats at PND15 (−8.2%, P = 0.0120) and PND28 (−26.2%, P < 0.0001) (Table 1).

Table 1.

Body weight and muscles weight measured in the control and sensorimotor restriction groups

PND15 PND28
CTRL (n = 20) SMR (n = 20) P value CTRL (n = 20) SMR (n = 19) P value
Body weight (g) 34.6 ± 3.7 31.7 ± 2.6 0.0120 91.5 ± 6.1 67.6 ± 5.5 <0.0001
Soleus weight (mg) 10.0 ± 1.6 6.8 ± 1.8 <0.0001 40.4 ± 4.5 18.1 ± 3.1 <0.0001
EDL weight (mg) 10.8 ± 1.9 10.7 ± 2.3 0.5333 44.9 ± 4.8 31.1 ± 4.0 <0.0001
Open in a new tab

CTRL, control group; SMR, sensorimotor restriction group; PND15, postnatal day 15; PND28, postnatal day 28.

At PND15, SMR induced an atrophy of the slow oxidative SOL muscle, with no effect in fast glycolytic EDL. By contrast, at PND28, the muscle weight relative to body weight was decreased for SOL muscle (−38.6%, P < 0.0001) and EDL muscle (−6.1%, P = 0.0301) (Fig. 1).

Figure 1. Soleus (SOL) and extensor digitorum longus (EDL) weight relative to body weight.

Figure 1

Open in a new tab

SOL and EDL weight relative to body weight according to the different groups and developmental stages. CTRL, control group; SMR, sensorimotor restriction group; PND15, postnatal day 15; PND28, postnatal day 28.

Muscle mitochondrial enzyme activities

CS activity is used as an indicator of the mitochondria amount. CS activity was reduced in the SOL of SMR rats at PND15 (−18%, P = 0.0047), whereas no change was detected at PND28. In the EDL, the CS activity was unchanged in SMR rats, regardless of age (Fig. 2A ).

Figure 2. Effect of SMR on mitochondrial enzyme activities and mitochondrial respiration in skeletal muscles.

Figure 2

Open in a new tab

Citrate synthase (CS) activity in the soleus (SOL) and the extensor digitorum longus (EDL) muscles at postnatal day 15 (PND15) and 28 (PND28) (A), complex activities in the SOL at PND15 and PND28 (B) and complex activities in the EDL at PND15 and PND28 (C), and mitochondrial respiration in the SOL and the EDL at PND28 (D). Data were standardized to the CTRL. CI, complex I; CII, complex II; CIV, complex IV.

Concerning the activity of mitochondrial complexes, which reflects the efficiency of the respiratory chain, complex II activity was only reduced in the SOL muscle of SMR rats at PND15 (−28%, P < 0.001), whereas, at PND28, both complex I and complex II activities were decreased (−24%, P = 0.0450 and −22%, P = 0.0356 respectively) (Fig. 2B ). By contrast, in the EDL muscle, a decrease of 19% was observed only in complex I activity at PND15 (P = 0.0179). No difference was observed at PND28 (Fig. 2C ).

Concerning the mitochondrial respiration at PND28, the JO2 driven by complex I (CI) or complexes I+II (CI+CII) was significantly lower in SMR rats than control rats (−47%, P = 0.0255 and −26%, P = 0.0457, respectively) in the soleus, without effect in the EDL (Fig. 2D ).

To determine how mitochondrial function evolves during the early development of the CTRL and SMR rats, mitochondrial enzymatic activities were compared at PND15 and PND28. The expression of mitochondrial enzyme activities relative to PND15 in both SMR and CTRL allows us to evaluate the influence of developmental evolution. The activity of the CS and of the mitochondrial complexes I and IV increased at PND28 with respect to PND15 in SOL muscle in CTRL (+65%, +432% and +321% respectively, P < 0.0001) and SMR (+132%, P < 0.0001, +295%, P < 0.001 and +348%, P = 0.0011, respectively) groups, whereas the activity of complex II was not modified in CTRL rats, or even slightly reduced (SMR rats, −35%, P = 0.0330) (Fig. 3A ).

Figure 3. Evolution of mitochondrial enzyme activities in skeletal muscles.

Figure 3

Open in a new tab

Evolution of citrate synthase (CS) and complex activities between postnatal day 15 (PND15) and 28 (PND28) in the soleus (SOL) (A) and the extensor digitorum longus (EDL) (B). Data were standardized to the PND15 stage. CTRL, control group; SMR, sensorimotor restriction group; CI, complex I; CII, complex II; CIV, complex IV.

The same pattern was observed in the EDL muscle. An increase in the activity of CS (+43% and +34% for CTRL and SMR rats, respectively, P < 0.0001), complex I (+182% and +160% for CTRL and SMR rats, respectively, P < 0.0001) and complex IV was observed (+232% and +165% for CTRL and SMR rats, respectively, P < 0.0001). However, in contrast to SOL muscle, complex II activity was increased in both CTRL (+63%, P < 0.0001) and SMR (+51%, P < 0.0001) rats (Fig. 3B ).

Mitochondrial enzyme activities in brain structures

To determine whether muscle changes are accompanied by changes in cerebral mitochondrial function, CS and mitochondrial complex activities were measured in different brain structures. The results showed structure‐specific changes and an age‐dependent response (Fig. 4). The full results are provided in the Supporting information (Table S1).

Figure 4. Effect of SMR on mitochondrial enzyme activities and mitochondrial respiration in brain structures.

Figure 4

Open in a new tab

Citrate synthase (CS) activity in the sensorimotor cortex (SM), the striatum (St), the prefrontal cortex (PF) and the hippocampus (Hi) at postnatal day 15 (PND15) and 28 (PND28) (A), and complex activities in the hippocampus at PND28 (B) and mitochondrial respiration in the sensorimotor cortex (SM), the prefrontal cortex (PF) and the hippocampus (Hi) at PND28 (C). Data were standardized to the control. CI, complex I; CII, complex II; CIV, complex IV.

At PND15, CS activity was higher in SMR rats than in CTRL rats in the sensorimotor cortex and the striatum (+15%, P < 0.001 and +13%, P = 0.0354, respectively), whereas no effect was observed in the prefrontal cortex and the hippocampus. By contrast, no SMR‐induced changes in CS activity were observed at PND28 for all structures (Fig. 4A ).

No effect on SMR was detected on mitochondrial complex activities at PND15 (data not shown). However, in the hippocampus, a significant decrease in complexes I and IV activity (−36%, P = 0.0260 and −26%, P = 0.0343, respectively) (Fig. 4B ) was observed at PND28.

In addition, early SMR altered mitochondrial respiration at PND28 in brain structures. Indeed, the JO2 driven by CI or CI+II was significantly lower in SMR rats than control rats (−30%, P = 0.0244 and −28%, P = 0.0246, respectively) in the sensorimotor cortex. In the hippocampus, the JO2 driven by CI and CI+CII was non‐significantly lower in SMR rats than control rats (−17%, P = 0.0879 and −16%, P = 0.1137, respectively). No difference was observed between the two groups in the prefrontal cortex (Fig. 4C ).

The evolution from PND15 to PND28 appeared to be structure‐specific and was not influenced by SMR (Fig. 5). Only CS activity was increased in all brain structures regardless of group (P < 0.0001). In the sensorimotor cortex, complex II activity was increased (+81% and +85% for CTRL and SMR rats, respectively, P < 0.0001), whereas complexes I and IV were increased only in CTRL rats (+51%, P = 0.0386 and +96%, P = 0.0328, respectively) (Fig. 5A ). In striatum, complex I activity was increased in both groups (+145% and +134%, respectively, P < 0.001) and complexes II and IV were increased only in SMR rats (+19%, P = 0.0259 and +161%, P = 0.0063 respectively) (Fig. 5B ). In prefrontal cortex, complex IV activity was significantly increased only in SMR group (+44%, P = 0.0365) (Fig. 5C ). In hippocampus, complex I activity was increased only in CTRL rats (+87% in CTRL group, P < 0.0001) and complex II activity was increased in both groups (+130% and +139% for CTRL and SMR rats, respectively, P < 0.0001) (Fig. 5D ).

Figure 5. Evolution of mitochondrial enzyme activities in brain structures.

Figure 5

Open in a new tab

Evolution of citrate synthase (CS) and complexes activities between postnatal day 15 (PND15) and 28 (PND28) in the sensorimotor cortex (A), the striatum (B), the prefrontal cortex (C) and the hippocampus (D). Data measured at PND28 were standardized to the PND15 stage. CI, complex I; CII, complex II; CIV, complex IV.

Discussion

Mitochondria play a central role in cellular energy metabolism, as well as other vital functions, including intracellular calcium regulation, redox signalling and apoptosis. Physical activity is crucial not only during childhood development, but also to protect brain function during ageing. Although emerging evidence supports a negative effect of sitting time on brain function (Carter et al., 2018; Tuckwell et al., 2022), understanding the cellular adaptations induced by inactivity and sedentary behaviour during development is crucial, especially regarding cerebral mitochondrial function. Therefore, the present study aimed to assess the effects of postnatal transient immobilization (SMR) on mitochondrial activities in rat muscle and brain. Our results showed in both groups an overall increase in mitochondrial enzyme activities during muscle and brain maturation, from PND15 to PND28, which is structure dependent. However, the main effects of SMR are (1) a decrease in mitochondrial enzyme activities that affects mainly the slow‐twitch SOL, with minor effects on the fast‐twitch EDL; (2) in the brain structures, an early (PND15) increase in CS activity in sensorimotor cortex whereas the hippocampus exhibited a reduction of mitochondrial enzyme activities at PND28; and, finally, (3) an early reduction in the mitochondrial respiration in the soleus and in the sensorimotor cortex, without effect in the EDL and the prefrontal cortex at PND28.

Effects of early SMR on muscle mitochondria

In the present study, SMR leads to a decrease in mitochondrial enzyme activities, mainly in the slow‐twitch SOL muscle and, to a lesser extent, in the fast‐twitch EDL. This is in accordance with Gram et al. (2014), who showed a decrease in activity of mitochondrial complexes I, II and III in young men after a 2 week immobilization. Concomitantly, the mitochondrial respiration was reduced in SOL muscle at PND28. Our data suggest a lower oxidative capacity of the SOL in SMR pups at both PND15 and PND28. These results may also reflect the transition of the phenotype towards the fast twitch fibres, as described previously (Canu et al., 2022).

CS is considered as a marker of mitochondrial abundance (Larsen et al., 2012). Interestingly, we observed a transient decrease in CS activity at PND15 for the SOL in response to SMR, whereas the CS level was similar in both groups at PND28, suggesting an adaptive mechanism. This observation contrasts with previous studies in human and animal models (Gram et al., 2014; Hyatt et al., 2019; Kang et al., 2016; Qi et al., 2012) that reported a decrease in response to an immobilization period. One main difference that may explain this discrepancy is the immobilization protocol. Although total immobilization was used to study mitochondrial function in previous studies, we used transient immobilization (16 h per day) because the aim of our study was to investigate the influence of a reduction of physical activity. Another difference is that our data were obtained during development rather than in adult animals suggesting that early SMR may delay the acquisition of a mature postural support (Dupuis et al., 2024).

The reduction in complex I and II activity at PND28 without any reduction in CS activity in SOL muscle suggests that qualitative adaptations occur in SMR conditions without mitochondrial amount variation. These adaptations support a phenotypic switch evidenced previously by muscle atrophy, a decrease in cross‐sectional area and a force loss following SMR (Canu et al., 2022).

Within the muscle, the evolution of mitochondrial enzyme activities between PND15 and PND28 is consistent with the increased energy demand during development and reveals an age‐related increase in oxidative capacity in these muscles. Our findings are consistent with previous studies that have shown a developmental increase in mitochondrial biogenesis and function in muscle during early postnatal growth, in particular from PND14 to PND42 (Kim et al., 2024, 2019). However, a notable difference in complex II activity is observed between the SOL and EDL muscles. In the SOL muscle of SMR rats, complex II activity decreases slightly, whereas, in the EDL muscle, it increases in both groups. These results are supported by previous studies showing that the evolution of mitochondrial function depends on the fibre type. For example, ageing, during which a reduction in physical activity is observed, leads to changes in mitochondrial functions. Picard et al. (2011) observed in aged rats altered mitochondrial‐driven free radical leak, mitochondrial calcium retention capacity or mitochondrial protein content that differed depending on fibre type. Further studies should elucidate the mechanisms underlying mitochondrial fibre type‐specific adaptations.

Effects of early SMR on brain mitochondria

Mitochondrial function is of interest during brain development and particularly during the processes of neurogenesis, neuronal differentiation, migration and maturation (Fame & Lehtinen, 2021). We examined several brain structures involved in cognitive (prefrontal cortex and hippocampus) and motor (sensorimotor cortex and striatum) functions, and we observed a decrease in mitochondrial enzyme activity (complexes I and IV) only in the hippocampus at PND28 and a decrease of CI and CI+II driven mitochondrial respiration in sensorimotor cortex. The lack of available results in the literature makes comparison difficult. Nevertheless, complexes I and IV in the hippocampus appear to be very sensitive to environmental factors such as physical activity. Indeed, these complexes are affected by ageing and Alzheimer's disease (Navarro & Boveris, 2010) and appear to be enhanced after physical exercise training. This negative effect of partial immobilization on mitochondrial complex activities appears to be region‐dependent in the brain. Indeed, immobilization does not appear to affect mitochondrial functions in the sensorimotor cortex. This result is probably because immobilization was partial, and the sensorimotor cortex was still involved in sensory and motor functions for part of the day. This is consistent with the fact that the neuroplasticity, often observed in the brain after a physical exercise program, is not uniform throughout the brain structures. For example, the hippocampus and prefrontal cortex regions in humans are most sensitive to ageing and physical exercise (Voelcker‐Rehage & Niemann, 2013; Weinstein et al., 2012; Yuki et al., 2012).

Surprisingly, in SMR pups, we observed an increase in CS activity at PND15 in the SM cortex and striatum, comprising structures mainly involved in motor function. This increase is in contrast with data obtained within the SOL muscle, but, as for muscle, this change was only transient because values similar to CTRL ones were recovered at PND28. This suggests that the reduction in rodent mobility delays mitochondrial ETC network development.

Potential underlying mechanisms

Many molecular mechanisms can influence mitochondrial biogenesis and function (Oliveira & Hood, 2019). The transcriptional coactivator PGC1α (i.e. peroxisome proliferator‐activated receptor gamma coactivator 1α) is considered to be a key regulator of mitochondrial biogenesis that interacts with the nuclear respiratory factor‐1 and 2 and mitochondrial transcription factor A pathways (Hood et al., 2016). Within the brain, the neural activity per se can activate these pathways (Yu & Yang, 2010), suggesting a thigh coupling between mitochondrial biogenesis and synaptic activity (Cardanho‐Ramos & Morais, 2021). Indeed, in adult mice, physical exercise improved mitochondrial biogenesis by activating PGC1α in the hippocampus (Steiner et al., 2011). The biogenesis and regulation of mitochondrial function are also influenced by molecules such as sirtuin that are either increased by activity or decreased by inactivity (Steiner et al., 2011). In addition, muscle‐derived exerkines may affect cerebral mitochondria, including BDNF, lactate, interleukin‐6, irisin and others (Heo et al., 2023). For example, BDNF binds to tropomyosin receptor kinase B (TrkB), its primary receptor, to form a complex that activates several signalling events (Miranda et al., 2019). Activation of TrkB by 7,8‐dihydroxyflavone has been shown to improve mitochondrial respiration in syncytiotrophoblasts from obese women (Prince et al., 2018). Moreover, BNDF has been shown to stimulate mitochondrial biogenesis and increase the respiratory control index in the rat brain through a mechanism involving complex I adaptations (Markham et al., 2004). Although exercise promotes BDNF expression in the brain (Sleiman et al., 2016), a sedentary lifestyle is generally associated with lower plasma BDNF levels (Júdice et al., 2021), supporting a potential interaction between activity/inactivity and brain plasticity. In a previous study, we did not report any change in brain BDNF level at PND15, nor PND28 in SMR rats (Dupuis et al., 2024), but the FNDC5/irisin level was increased at PND15 in the prefrontal cortex, hippocampus and striatum and returned to CTRL levels at PND28. Because FNCD5 expression is also stimulated by PGC1a (Wrann et al., 2013) and given that irisin stimulates the cAMP/PKA signalling pathways (Lourenco et al., 2019), which is also involved in mitochondrial biogenesis, we could speculate that a negative feedback loop may be activated by inactivity. Hence, the quantitative mitochondrial adaptations induced by the SMR condition at PND15 would result from the higher level of irisin. Overall, changes in exerkine levels might explain the upregulation of mitochondrial biogenesis during immobilization and require further studies.

Furthermore, we have shown that the evolution of mitochondrial complex activities is structure‐dependent. By contrast, for CS, the rate is rising in all structures. This age‐dependent increase suggests ongoing mitochondrial maturation and an increase in mitochondrial content with postnatal development independently of altered environmental stimulations, as a situation of SMR.

Given that mitochondrial function is highly modulated by physical exercise (Marques‐Aleixo et al., 2012), it could be considered that the time interval between cast removal and muscle sampling could influence the results. In fact, during this period (2 h maximum), the animals could move freely introducing a possible bias. This concern is supported by findings from Yoo et al. (2019), who observed that mitochondrial respiration in skeletal muscle can increase within just 1 h of exercise. However, because our results indicate a decrease in mitochondrial respiration in muscle and brain structures, we hypothesise that this transient post‐cast removal activity may underestimate the true extent of the reduction induced by immobilization.

Limits

On the whole, the present study has shown a negative impact of SMR on muscle and brain mitochondrial function. This might be explained by the opposite effect of development, which increases mitochondrial activity (Almeida et al., 1995; Land et al., 1977), and immobilization, which probably has a negative impact. However, although the effect of physical activity on the adult brain is well documented, data on immobilization are very scarce. Although the present study provides valuable insights, further investigations are required to fully understand the molecular adaptations to SMR. We acknowledge that the transfer to humans is tricky, and the immobilization of the rats in the present study does not fully reflect a sedentary lifestyle during brain maturation. Moreover, complementary measurements such as mitochondrial protein levels and mitochondrial dynamics may help to understand the mitochondrial adaptations. A full assessment of mitochondrial function in all brain tissues and at PND15 would contribute to a more comprehensive understanding of sedentary behaviour on mitochondria and the tissue‐specific responses. It is important to note that, in the present study, the experiments were conducted during the growth phase of the animals, comprising a period characterized by unique neurophysiological and developmental dynamics. Therefore, the results may not be extrapolated to adult populations, where different adaptations may occur. Future research should investigate these effects in mature individuals aiming to provide a more comprehensive understanding of brain mitochondrial plasticity.

In conclusion, the present study provides valuable insights into mitochondrial adaptations to restricted activity during growth in rat muscle and brain structures. Early SMR in rats appears to induce mitochondrial alterations in skeletal muscles and certain brain structures involved in cognitive and motor processes. These findings are particularly compelling given the increasing prevalence of sedentary lifestyles, highlighting the importance of physical activity, particularly during childhood, to prevent early brain metabolic disturbances.

Additional information

Competing interests

The authors declare that they have no competing interests.

Author contributions

E.D., M.‐H.C. and F.D. were responsible for the conception or design of the work. M.V.G., O.D., E.D., M.‐H.C. and F.D. were responsible for the acquisition, analysis or interpretation of data. O.D., M.V.G., E.D., M.‐H.C. and F.D. were responsible for drafting the work or revising it critically for important intellectual content. All authors have read and approved the final version of this manuscript submitted for publication and agree to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. All persons designated as authors qualify for authorship and all those who qualify for authorship are listed.

Funding

No funding was received.

Supporting information

Peer Review History

TJP-604-2512-s002.pdf (372.6KB, pdf)

Table S1 Full results of mitochondrial enzyme activities (citrate synthase and complexes I, II and IV) in both groups at PND15 and PND28

TJP-604-2512-s001.docx (16.8KB, docx)

Biographies

Melanie Van Gaever completed her Master's degree in Biology‐Health at the University of Lille in 2022. She is currently a PhD student in the URePSSS laboratory. Her research investigates the role of physical activity as a countermeasure to hypoactivity in neonatal rats. Using the sensorimotor restriction model, she studies its effects on mitochondrial metabolism, as well as cognitive and motor behaviours.

graphic file with name TJP-604-2512-g007.gif

Olivier Dupuy is an Associate Professor in exercise physiology at the Faculty of Sports at the University of Poitiers and the Faculty of Medicine of the University of Montreal, interested in the relationship between physical activity and cognitive functions through neuroscience. He is interested in heart–brain relationships and their modulation to acute and chronic exercise. He is also interested in the influences of cerebral haemodynamics response to physical exercise and their impact on cognitive enhancement.

graphic file with name TJP-604-2512-g001.gif

Handling Editors: Karyn Hamilton & Rebecca MacPherson

The peer review history is available in the Supporting Information section of this article (https://doi.org/10.1113/JP287765#support‐information‐section).

Data availability statement

Data are available from the corresponding author upon reasonable request.

References

  1. Almeida, A. , Brooks, K. J. , Sammut, I. , Keelan, J. , Davey, G. P. , Clark, J. B. , & Bates, T. E. (1995). Postnatal development of the complexes of the electron transport chain in synaptic mitochondria from rat brain. Developmental Neuroscience, 17(4), 212–218. [DOI] [PubMed] [Google Scholar]
  2. Bartman, S. , Coppotelli, G. , & Ross, J. M. (2024). Mitochondrial dysfunction: A key player in brain aging and diseases. Current Issues in Molecular Biology, 46(3), 1987–2026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bernardo, T. C. , Marques‐Aleixo, I. , Beleza, J. , Oliveira, P. J. , Ascensão, A. , & Magalhães, J. (2016). Physical exercise and brain mitochondrial fitness: The possible role against Alzheimer's disease. Brain Pathology (Zurich, Switzerland), 26(5), 648–663. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Burtscher, J. , Millet, G. P. , Place, N. , Kayser, B. , & Zanou, N. (2021). The muscle‐brain axis and neurodegenerative diseases: The key role of mitochondria in exercise‐induced neuroprotection. International Journal of Molecular Sciences, 22(12), 6479. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Burtscher, J. , Romani, M. , Bernardo, G. , Popa, T. , Ziviani, E. , Hummel, F. C. , Sorrentino, V. , & Millet, G. P. (2022). Boosting mitochondrial health to counteract neurodegeneration. Progress in Neurobiology, 215, 102289. [DOI] [PubMed] [Google Scholar]
  6. Canu, M. H. , Montel, V. , Dereumetz, J. , Marqueste, T. , Decherchi, P. , Coq, J. O. , Dupont, E. , & Bastide, B. (2022). Early movement restriction deteriorates motor function and soleus muscle physiology. Experimental Neurology, 347, 113886. [DOI] [PubMed] [Google Scholar]
  7. Cardanho‐Ramos, C. , & Morais, V. A. (2021). Mitochondrial Biogenesis in Neurons: How and Where. International Journal of Molecular Sciences, 22(23), 13059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Carter, S. E. , Draijer, R. , Holder, S. M. , Brown, L. , Thijssen, D. H. J. , & Hopkins, N. D. (2018). Regular walking breaks prevent the decline in cerebral blood flow associated with prolonged sitting. Journal of Applied Physiology (Bethesda, Md. : 1985), 125(3), 790–798. [DOI] [PubMed] [Google Scholar]
  9. Delcour, M. , Massicotte, V. S. , Russier, M. , Bras, H. , Peyronnet, J. , Canu, M. H. , Cayetanot, F. , Barbe, M. F. , & Coq, J. O. (2018). Early movement restriction leads to enduring disorders in muscle and locomotion. Brain Pathology (Zurich, Switzerland), 28(6), 889–901. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Dietrich, M. O. , Andrews, Z. B. , & Horvath, T. L. (2008). Exercise‐induced synaptogenesis in the hippocampus is dependent on UCP2‐regulated mitochondrial adaptation. Journal of Neuroscience, 28(42), 10766–10771. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Dupuis, O. , Van Gaever, M. , Montel, V. , Dereumetz, J. , Coq, J. O. , Canu, M. H. , & Dupont, E. (2024). Early movement restriction affects the acquisition of neurodevelopmental reflexes in rat pups. Brain Research, 1828, 148773. [DOI] [PubMed] [Google Scholar]
  12. Fame, R. M. , & Lehtinen, M. K. (2021). Mitochondria in early forebrain development: From neurulation to mid‐corticogenesis. Frontiers in Cell and Developmental Biology, 9, 780207. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Gram, M. , Vigelsø, A. , Yokota, T. , Hansen, C. N. , Helge, J. W. , Hey‐Mogensen, M. , & Dela, F. (2014). Two weeks of one‐leg immobilization decreases skeletal muscle respiratory capacity equally in young and elderly men. Experimental Gerontology, 58, 269–278. [DOI] [PubMed] [Google Scholar]
  14. Heo, J. , Noble, E. E. , & Call, J. A. (2023). The role of exerkines on brain mitochondria: A mini‐review. Journal of Applied Physiology (Bethesda, Md.: 1985), 134(1), 28–35. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Hollville, E. , Romero, S. E. , & Deshmukh, M. (2019). Apoptotic cell death regulation in neurons. The FEBS Journal, 286(17), 3276–3298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Hood, D. A. , Tryon, L. D. , Carter, H. N. , Kim, Y. , & Chen, C. C. (2016). Unravelling the mechanisms regulating muscle mitochondrial biogenesis. The Biochemical Journal, 473(15), 2295–2314. [DOI] [PubMed] [Google Scholar]
  17. Hyatt, H. , Deminice, R. , Yoshihara, T. , & Powers, S. K. (2019). Mitochondrial dysfunction induces muscle atrophy during prolonged inactivity: A review of the causes and effects. Archives of Biochemistry and Biophysics, 662, 49–60. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Júdice, P. B. , Magalhães, J. P. , Hetherington‐Rauth, M. , Correia, I. R. , & Sardinha, L. B. (2021). Sedentary patterns are associated with BDNF in patients with type 2 diabetes mellitus. European Journal of Applied Physiology, 121(3), 871–879. [DOI] [PubMed] [Google Scholar]
  19. Kang, C. , Yeo, D. , & Ji, L. L. (2016). Muscle immobilization activates mitophagy and disrupts mitochondrial dynamics in mice. Acta Physiologica (Oxford, England), 218(3), 188–197. [DOI] [PubMed] [Google Scholar]
  20. Kim, Y. , Parry, H. A. , Willingham, T. B. , Alspaugh, G. , Lindberg, E. , Combs, C. A. , Knutson, J. R. , Bleck, C. K. E. , & Glancy, B. (2024). Reorganization of mitochondria‐organelle interactions during postnatal development in skeletal muscle. The Journal of Physiology, 602(5), 891–912. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kim, Y. , Yang, D. S. , Katti, P. , & Glancy, B. (2019). Protein composition of the muscle mitochondrial reticulum during postnatal development. The Journal of Physiology, 597(10), 2707–2727. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Lamoureux, N. R. , Fitzgerald, J. S. , Norton, K. I. , Sabato, T. , Tremblay, M. S. , & Tomkinson, G. R. (2019). Temporal trends in the cardiorespiratory fitness of 2,525,827 adults between 1967 and 2016: A systematic review. Sports Medicine (Auckland, NZ), 49(1), 41–55. [DOI] [PubMed] [Google Scholar]
  23. Land, J. M. , Booth, R. F. , Berger, R. , & Clark, J. B. (1977). Development of mitochondrial energy metabolism in rat brain. The Biochemical Journal, 164(2), 339–348. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Larsen, S. , Nielsen, J. , Hansen, C. N. , Nielsen, L. B.o , Wibrand, F. , Stride, N. , Schroder, H. D. , Boushel, R. , Helge, J. W. , Dela, F. , & Hey‐Mogensen, M. (2012). Biomarkers of mitochondrial content in skeletal muscle of healthy young human subjects. The Journal of Physiology, 590(14), 3349–3360. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lourenco, M. V. , Frozza, R. L. , De Freitas, G. B. , Zhang, H. , Kincheski, G. C. , Ribeiro, F. C. , Gonçalves, R. A. , Clarke, J. R. , Beckman, D. , Staniszewski, A. , Berman, H. , Guerra, L. A. , Forny‐Germano, L. , Meier, S. , Wilcock, D. M. , De Souza, J. M. , Alves‐Leon, S. , Prado, V. F. , Prado, M. A. M. , … De Felice, F. G. (2019). Exercise‐linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nature Medicine, 25(1), 165–175. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Luhmann, H. J. (2021). Neurophysiology of the developing cerebral cortex: What we have learned and what we need to know. Frontiers in Cellular Neuroscience, 15, 814012. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Magistretti, P. J. , & Allaman, I. (2015). A cellular perspective on brain energy metabolism and functional imaging. Neuron, 86(4), 883–901. [DOI] [PubMed] [Google Scholar]
  28. Markham, A. , Cameron, I. , Franklin, P. , & Spedding, M. (2004). BDNF increases rat brain mitochondrial respiratory coupling at complex I, but not complex II. European Journal of Neuroscience, 20(5), 1189–1196. [DOI] [PubMed] [Google Scholar]
  29. Marques‐Aleixo, I. , Oliveira, P. J. , Moreira, P. I. , Magalhães, J. , & Ascensão, A. (2012). Physical exercise as a possible strategy for brain protection: evidence from mitochondrial‐mediated mechanisms. Progress in Neurobiology, 99(2), 149–162. [DOI] [PubMed] [Google Scholar]
  30. Miranda, M. , Morici, J. F. , Zanoni, M. B. , & Bekinschtein, P. (2019). Brain‐Derived neurotrophic factor: A key molecule for memory in the healthy and the pathological brain. Frontiers in Cellular Neuroscience, 13, 363. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Navarro, A. , & Boveris, A. (2010). Brain mitochondrial dysfunction in aging, neurodegeneration, and Parkinson's disease. Frontiers in Aging Neuroscience, 2, 34. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. O'reilly, C. L. , Miller, B. F. , & Lewis, T. L. (2023). Exercise and mitochondrial remodeling to prevent age‐related neurodegeneration. Journal of Applied Physiology (Bethesda, Md.: 1985), 134(1), 181–189. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Olds, T. , Tomkinson, G. , Léger, L. , & Cazorla, G. (2006). Worldwide variation in the performance of children and adolescents: an analysis of 109 studies of the 20‐m shuttle run test in 37 countries. Journal of Sports Sciences, 24(10), 1025–1038. [DOI] [PubMed] [Google Scholar]
  34. Oliveira, A. N. , & Hood, D. A. (2019). Exercise is mitochondrial medicine for muscle. Sports Medicine and Health Science, 1(1), 11–18. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Picard, M. , Ritchie, D. , Thomas, M. M. , Wright, K. J. , & Hepple, R. T. (2011). Alterations in intrinsic mitochondrial function with aging are fiber type‐specific and do not explain differential atrophy between muscles. Aging Cell, 10(6), 1047–1055. [DOI] [PubMed] [Google Scholar]
  36. Prince, C. S. , Maloyan, A. , & Myatt, L. (2018). Tropomyosin receptor kinase B agonist, 7,8‐Dihydroxyflavone, improves mitochondrial respiration in placentas from obese women. Reproductive Sciences, 25(3), 452–462. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Qi, Z. , Zhang, Y. , Guo, W. , Ji, L. , & Ding, S. (2012). Increased insulin sensitivity and distorted mitochondrial adaptations during muscle unloading. International Journal of Molecular Sciences, 13(12), 16971–16985. [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Reutzel, M. , Grewal, R. , Dilberger, B. , Silaidos, C. , Joppe, A. , & Eckert, G. P. (2020). Cerebral mitochondrial function and cognitive performance during aging: A longitudinal study in NMRI mice. Oxidative Medicine and Cellular Longevity, 2020, 4060769. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Semple, B. D. , Blomgren, K. , Gimlin, K. , Ferriero, D. M. , & Noble‐Haeusslein, L. J. (2013). Brain development in rodents and humans: Identifying benchmarks of maturation and vulnerability to injury across species. Progress in Neurobiology, 106–107, 1–16. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Sleiman, S. F. , Henry, J. , Al‐Haddad, R. , El Hayek, L. , Abou Haidar, E. , Stringer, T. , Ulja, D. , Karuppagounder, S. S. , Holson, E. B. , Ratan, R. R. , Ninan, I. , & Chao, M. V. (2016). Exercise promotes the expression of brain derived neurotrophic factor (BDNF) through the action of the ketone body β‐hydroxybutyrate. eLife, 5, e15092. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Stamatakis, E. , Gale, J. , Bauman, A. , Ekelund, U. , Hamer, M. , & Ding, D. (2019). Sitting time, physical activity, and risk of mortality in adults. Journal of the American College of Cardiology, 73(16), 2062–2072. [DOI] [PubMed] [Google Scholar]
  42. Steiner, J. L. , Murphy, E. A. , McClellan, J. L. , Carmichael, M. D. , & Davis, J. M. (2011). Exercise training increases mitochondrial biogenesis in the brain. Journal of Applied Physiology (Bethesda, Md.: 1985), 111(4), 1066–1071. [DOI] [PubMed] [Google Scholar]
  43. Tomkinson, G. R. (2007). Global changes in anaerobic fitness test performance of children and adolescents (1958–2003). Scandinavian Journal of Medicine & Science in Sports, 17(5), 497–507. [DOI] [PubMed] [Google Scholar]
  44. Tuckwell, G. A. , Vincent, G. E. , Gupta, C. C. , & Ferguson, S. A. (2022). Does breaking up sitting in office‐based settings result in cognitive performance improvements which last throughout the day? A review of the evidence. Industrial Health, 60(6), 501–513. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Voelcker‐Rehage, C. , & Niemann, C. (2013). Structural and functional brain changes related to different types of physical activity across the life span. Neuroscience and Biobehavioral Reviews, 37(9), 2268–2295. [DOI] [PubMed] [Google Scholar]
  46. Weinstein, A. M. , Voss, M. W. , Prakash, R. S. , Chaddock, L. , Szabo, A. , White, S. M. , Wojcicki, T. R. , Mailey, E. , McAuley, E. , Kramer, A. F. , & Erickson, K. I. (2012). The association between aerobic fitness and executive function is mediated by prefrontal cortex volume. Brain, Behavior, and Immunity, 26(5), 811–819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. World Health Organization . (2022). Global status on physical activity 2022. Geneva, Switzerland. [Google Scholar]
  48. Wrann, C. D. , White, J. P. , Salogiannnis, J. , Laznik‐Bogoslavski, D. , Wu, J. , Ma, D. , Lin, J. D. , Greenberg, M. E. , & Spiegelman, B. M. (2013). Exercise induces hippocampal BDNF through a PGC‐1alpha/FNDC5 pathway. Cell Metabolism, 18(5), 649–659. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Yoo, S. Z. , No, M. H. , Heo, J. W. , Park, D. H. , Kang, J. H. , Kim, J. H. , Seo, D. Y. , Han, J. , Jung, S. J. , & Kwak, H. B. (2019). Effects of acute exercise on mitochondrial function, dynamics, and mitophagy in rat cardiac and skeletal muscles. International Neurourology Journal, 23, (Suppl 1), S22–S31. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Yu, L. , & Yang, S. J. (2010). AMP‐activated protein kinase mediates activity‐dependent regulation of peroxisome proliferator‐activated receptor gamma coactivator‐1alpha and nuclear respiratory factor 1 expression in rat visual cortical neurons. Neuroscience, 169(1), 23–38. [DOI] [PubMed] [Google Scholar]
  51. Yuki, A. , Lee, S. , Kim, H. , Kozakai, R. , Ando, F. , & Shimokata, H. (2012). Relationship between physical activity and brain atrophy progression. Medicine and Science in Sports and Exercise, 44(12), 2362–2368. [DOI] [PubMed] [Google Scholar]
  52. Zeiss, C. J. (2021). Comparative milestones in rodent and human postnatal central nervous system development. Toxicologic Pathology, 49(8), 1368–1373. [DOI] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Peer Review History

TJP-604-2512-s002.pdf (372.6KB, pdf)

Table S1 Full results of mitochondrial enzyme activities (citrate synthase and complexes I, II and IV) in both groups at PND15 and PND28

TJP-604-2512-s001.docx (16.8KB, docx)

Data Availability Statement

Data are available from the corresponding author upon reasonable request.

Articles from The Journal of Physiology are provided here courtesy of Wiley

RESOURCES