The transcriptional coregulator PGC-1β controls mitochondrial function and anti-oxidant defence in skeletal muscles

Abstract

The transcriptional coregulators PGC-1α and PGC-1β modulate the expression of numerous partially overlapping genes involved in mitochondrial biogenesis and energetic metabolism. The physiological role of PGC-1β is poorly understood in skeletal muscle, a tissue of high mitochondrial content to produce ATP levels required for sustained contractions. Here we determine the physiological role of PGC-1β in skeletal muscle using mice, in which PGC-1β is selectively ablated in skeletal myofibres at adulthood (PGC-1β(i)skm−/− mice). We show that myofibre myosin heavy chain composition and mitochondrial number, muscle strength and glucose homeostasis are unaffected in PGC-1β(i)skm−/− mice. However, decreased expression of genes controlling mitochondrial protein import, translational machinery and energy metabolism in PGC-1β(i)skm−/− muscles leads to mitochondrial structural and functional abnormalities, impaired muscle oxidative capacity and reduced exercise performance. Moreover, enhanced free-radical leak and reduced expression of the mitochondrial anti-oxidant enzyme Sod2 increase muscle oxidative stress. PGC-1β is therefore instrumental for skeletal muscles to cope with high energetic demands.

MyoD Regulates Skeletal Muscle Oxidative Metabolism Cooperatively with Alternative NF-κB

“…We tested this notion in vivo by knocking down expression of PGC-1β alone, MyoD alone, or PGC-1β together with MyoD in TA muscles (Figure 6A). Consistent with PGC-1β being an important regulator of muscle metabolic homeostasis (Gali Ramamoorthy et al, 2015), PGC-1β knockdown alone was sufficient to reduce muscle OCR and expression of several mitochondrial genes (Figures 6B and 6C). In comparison, the knockdown of MyoD further reduced both OCR and mitochondrial gene expression (Figures 6B and 6C), suggesting that PGC-1β is not the only transcriptional target mediating the impact of MyoD on oxidative metabolism.…”

Acute Exercise Stimulates Carnitine Biosynthesis and OCTN2 Expression in Mouse Kidney

“…Also noted was an increase in PGC-1β mRNA expression, suggesting that mitochondrial respiration was increased by the stimulus of acute exercise [20]. Elevated use of FAs is consistent with the increased levels of esterified carnitine detected at the end of the exercise session and reported in earlier studies [5, 6, 25].…”

“…As illustrated in figure 5, expression of CPT-1a was increased by ∼50%, although non-significantly, at 4 hours into recovery. However, gene expression of peroxisome proliferator-activated receptor-γ coactivator 1 (PGC-1β) was significantly increased, indicating that mitochondrial respiratory function was stimulated by the exercise session [20]. …”

Muscular dystrophy in PTFR/cavin-1 null mice

“…One possibility is that the decrease in type IIa myofiber contributed the most to the decreased oxidative capacity in KO muscle, rather than type I fiber. It has been reported that the soleus muscles of mice had predominantly fast-oxidative type IIa fibers, followed by the slow-oxidative type I fibers, and very low percentages of glycolytic IIx/IIb types (52). Moreover, IIa and many IIx fibers could have a higher SDH activity than type I fibers in mouse and rat muscle (53).…”