Skeletal Muscle-Specific Overexpression of PGC-1α Induces Fiber-Type Conversion through Enhanced Mitochondrial Respiration and Fatty Acid Oxidation in Mice and Pigs

Abstract

Individual skeletal muscles in the animal body are heterogeneous, as each is comprised of different fiber types. Type I muscle fibers are rich with mitochondria, and have high oxidative metabolisms while type IIB fibers have few mitochondria and high glycolytic metabolic capacity. Peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α), a transcriptional co-activator that regulates mitochondrial biogenesis and respiratory function, is implicated in muscle fiber-type switching. Over-expression of PGC-1α in transgenic mice increased the proportion of red/oxidative type I fiber. During pig muscle growth, an increased number of type I fibers can give meat more red color. To explore the roles of PGC-1α in regulation of muscle fiber type conversion, we generated skeletal muscle-specific PGC-1α transgenic mice and pig. Ectopic over-expression of PGC-1α was detected in both fast and slow muscle fibers. The transgenic animals displayed a remarkable amount of red/oxidative muscle fibers in major skeletal muscle tissues. Skeletal muscles from transgenic mice and pigs have increased expression levels of oxidative fiber markers such as MHC1, MHC2x, myoglobin and Tnni1, and decreased expressions of glycolytic fiber genes (MHC2a, MHC2b, CASQ-1 and Tnni2). The genes responsible for the TCA cycle and oxidative phosphorylation, cytochrome coxidase 2 and 4, and citrate synthase were also increased in the transgenic mice and pigs. These results suggested that transgenic over-expressed PGC-1α significantly increased muscle mitochondrial biogenesis, resulting in qualitative changes from glycolytic to oxidative energy generation. The transgenic animals also had elevated levels of PDK4 and PPARγ proteins in muscle tissue, which can lead to increased glycogen deposition and fatty acid oxidation. Therefore, the results support a significant role of PGC-1α in conversion of fast glycolytic fibers to slow and oxidative fiber through enhanced mitochondrial respiration and fatty acid oxidation, and transgenic over-expression of PGC-1α in skeletal muscle leads to more red meat production in pigs.

6‐Gingerol Improves Ectopic Lipid Accumulation, Mitochondrial Dysfunction, and Insulin Resistance in Skeletal Muscle of Ageing Rats: Dual Stimulation of the AMPK/PGC‐1α Signaling Pathway via Plasma Adiponectin and Muscular AdipoR1

“…PGC‐1α is known to induce a fast‐ to slow‐fiber type transition through its activation of target genes involved in substrate metabolism . Skeletal muscle‐specific overexpression of PGC‐1α induces fiber‐type conversion through enhanced mitochondrial respiration and fatty acid oxidation in mice and pigs . Therefore, our results suggest that oral 6‐gingerol not only improves mitochondrial dysfunctional structure but also increases high endurance type I fiber (MyHC1) content by activating AMPK/PGC‐1α signaling to enhance mitochondrial function and muscle oxidative capacity in ageing rats.…”

Effects of intermittent hyperbaric exposure on endurance and interval exercise performance in well‐trained mice

“…PPARβ was shown to be required for the formation and maintenance of slow oxidative fibres in skeletal muscles by stimulating PGC‐1α expression (Schuler et al., ). The overexpression of PGC‐1α was previously reported to increase the proportion of type I fibres in the gastrocnemius muscle (Lin et al., ; Zhang et al., ). In the present study, increases in the proportion of type I fibres were observed in SOL only (Table ).…”

“…PGC‐1α also contributes to the changes induced in muscle fibre type by exercise training. Although the muscle‐specific deletion of PGC‐1α did not affect exercise‐induced fibre type transformation (Geng et al., ), the overexpression of PGC‐1α was shown to increase the proportion of type I fibres in skeletal muscle (Lin et al., ; Zhang et al., ).…”

Leucine regulates slow‐twitch muscle fibers expression and mitochondrial function by Sirt1/AMPK signaling in porcine skeletal muscle satellite cells

“…However, our data indicated that inhibition of AMPK and Sirt1 significantly attenuated the leucine‐induced increase in the expression of mitochondrial biogenesis and function‐related genes, suggesting that leucine modulated mitochondrial biogenesis via Sirt1/AMPK signaling, which is consistent with a previous study in C2C12 cells (Lin et al., ). Additionally, a recent in vitro study also found that skeletal muscle‐specific overexpression of PGC‐1α promotes the formation of slow‐twitch muscle fibers through enhanced mitochondrial function in mice and pigs (Zhang et al., ). However, whether leucine increases the expression of slow oxidative fiber by changing the mitochondrial function needs to be further investigated.…”