Sirt6 reprograms myofibers to oxidative type through CREB-dependent Sox6 suppression

Abstract

Expanding the exercise capacity of skeletal muscle is an emerging strategy to combat obesity-related metabolic diseases and this can be achieved by shifting skeletal muscle fibers toward slow-twitch oxidative type. Here, we report that Sirt6, an anti-aging histone deacetylase, is critical in regulating myofiber configuration toward oxidative type and that Sirt6 activator can be an exercise mimetic. Genetic inactivation of Sirt6 in skeletal muscle reduced while its transgenic overexpression increased mitochondrial oxidative capacity and exercise performance in mice. Mechanistically, we show that Sirt6 downregulated Sox6, a key repressor of slow fiber specific gene, by increasing the transcription of CREB. Sirt6 expression is elevated in chronically exercised humans and mice treated with an activator of Sirt6 showed an increase in exercise endurance as compared to exercise-trained controls. Thus, the current study identifies Sirt6 as a new molecular target for reprogramming myofiber composition toward the oxidative type and for improving muscle performance.

PRMT5 links lipid metabolism to contractile function of skeletal muscles

“…Muscle fiber type switching occurs in response to a variety of genetic, physiological, and metabolic condition (Schiaffino & Reggiani, 2011 ). A decrease in the proportion of slow‐oxidative myofibers is, in general, correlated with reduced exercise plasticity (Park et al , 2021 ). Several PRMTs have been reported to affect fiber type composition (Stouth et al , 2018 ).…”

“…Oxidative myofibers normally have a higher mitochondrial content than glycolytic myofibers to enable cellular energy production through oxidative phosphorylation (Hawley, 2002 ). In pharmacological and genetic inactivation studies in vivo , mitochondrial enzyme activity has been shown to be positively associated with exercise capacity (Marcinko et al , 2015 ; Park et al , 2021 ). Consistently, the reduction in oxidative phosphorylation in skeletal muscle tissues and reduced OCR in myofibers of Prmt5 MKO mice are associate with reduced exercise performance.…”

PRMT5 links lipid metabolism to contractile function of skeletal muscles

“…Muscle fiber type switching occurs in response to a variety of genetic, physiological, and metabolic condition 50 . A decrease in the proportion of slow-oxidative myofibers is, in general, correlated with reduced exercise plasticity 51 . Several PRMTs have been reported to affect fiber type composition 52 .…”

“…Oxidative myofibers normally have a higher mitochondrial content than glycolytic myofibers to enable cellular energy production through oxidative phosphorylation 53 . In pharmacological and genetic inactivation studies in vivo, mitochondrial enzyme activity has been shown to be positively associated with exercise capacity 51,54 . Our finding indicated a reduction in oxidative phosphorylation in skeletal muscle tissues, as well as reduced OCR in Prmt5 MKO myocytes.…”