Impaired exercise tolerance, mitochondrial biogenesis, and muscle fiber maintenance in miR‐133a–deficient mice

Abstract

Exercise promotes multiple beneficial effects on muscle function, including induction of mitochondrial biogenesis. miR-133a is a muscle-enriched microRNA that regulates muscle development and function. The role of miR-133a in exercise tolerance has not been fully elucidated. In the current study, mice that were deficient in miR-133a demonstrated low maximal exercise capacity and low resting metabolic rate. Transcription of the mitochondrial biogenesis regulators peroxisome proliferator-activated receptor-γ coactivator 1-α, peroxisome proliferator-activated receptor-γ coactivator 1-β, nuclear respiratory factor-1, and transcription factor A, mitochondrial were lower in miR-133a-deficient muscle, which was consistent with lower mitochondrial mass and impaired exercise capacity. Six weeks of endurance exercise training increased the transcriptional level of miR-133a and stimulated mitochondrial biogenesis in wild-type mice, but failed to improve mitochondrial function in miR-133a-deficient mice. Further mechanistic analysis showed an increase in the miR-133a potential target, IGF-1 receptor, along with hyperactivation of Akt signaling, in miR-133a-deficient mice, which was consistent with lower transcription of the mitochondrial biogenesis regulators. These findings indicate an essential role of miR-133a in skeletal muscle mitochondrial biogenesis, exercise tolerance, and response to exercise training.-Nie, Y., Sato, Y., Wang, C., Yue, F., Kuang, S., Gavin, T. P. Impaired exercise tolerance, mitochondrial biogenesis, and muscle fiber maintenance in miR-133a-deficient mice.

Evaluation of Muscle Performance in Mice by Treadmill Exhaustion Test and Whole-limb Grip Strength Assay

“…Other parameters such as work and power can additionally be used (Nie et al ., 2016). Work and power are calculated as follows: $$\begin{array}{l}\text{Work}false(\mathrm{normalJ}false)=\text{body}\text{mass}false(\text{kg}false)\times \text{gravity}false(9.81\mathrm{normalm}/{sec}^{2}false)\times \text{vertical}\text{speed}false(\mathrm{normalm}/sec\times \text{angle}false)\times \text{time}false(secfalse)\\ \text{Power}false(\mathrm{normalW}false)=\text{work}false(\mathrm{normalJ}false)/\text{time}false(secfalse)\end{array}$$…”

“…In this instrument the angle of inclination is set by the location of the spring pin in holes of the inclination rod. Uphill inclinations (slopes of 10%) are commonly used for this test (Bi et al , 2016; Nie et al , 2016; Yue et al , 2016). Uphill running involves concentric muscle contraction and increases the muscle work for the animals as compared with running on a flat surface, leading to faster exhaustion.…”

“…For example, the effects of aerobic exercise can be evaluated by exercising the animals for 60 min at 14 m/min on a 10% grade, 5 day/week, for 6 weeks (Nie et al ., 2016). The modification on the angle of the treadmill would enable the study of the outcomes of uphill (incline-slope, concentric) and downhill (decline-slope, eccentric) running.…”

Role of microRNAs on the Regulation of Mitochondrial Biogenesis and Insulin Signaling in Skeletal Muscle

“…The expression of miR‐23 was markedly reduced, whereas the expressions of miR‐181, 1, and 107 were markedly upregulated, as judged by the increased expression of PGC1α, as well as several of its downstream targets, including the electron transport chain protein, cytochrome c. In addition, mice deficient in miR‐133a were demonstrated to exhibited low exercise capacity, an effect that was consistent with a low transcription of PGC1α, PGC1β, NRF‐1, and TFAM. In contrast, endurance exercise training increased the transcriptional level of miR‐133a indicating that miR‐133a plays an essential role in skeletal muscle mitochondrial biogenesis (Nie et al, ). Taken together, these findings reveal an extensive and integrated network of functional interactions between the miR‐181, 1, 23, 107, and miR‐133a and their respective targets to regulate mitochondrial biogenesis and response to exercise training.…”

Muscle Histology Characterization Using H&E Staining and Muscle Fiber Type Classification Using Immunofluorescence Staining

“…A panel of monoclonal antibodies can be used to specifically label these muscle fiber subtypes. These protocols are commonly used in the study of muscle development, growth and regeneration (for example: Wang et al , 2015; Nie et al , 2016; Yue et al , 2016; Wang et al , 2017). …”