Mitochondrial energy deficiency leads to hyperproliferation of skeletal muscle mitochondria and enhanced insulin sensitivity

Abstract

Diabetes is associated with impaired glucose metabolism in the presence of excess insulin. Glucose and fatty acids provide reducing equivalents to mitochondria to generate energy, and studies have reported mitochondrial dysfunction in type II diabetes patients. If mitochondrial dysfunction can cause diabetes, then we hypothesized that increased mitochondrial metabolism should render animals resistant to diabetes. This was confirmed in mice in which the heart-muscle-brain adenine nucleotide translocator isoform 1 (ANT1) was inactivated. ANT1-deficient animals are insulin-hypersensitive, glucose-tolerant, and resistant to high fat diet (HFD)-induced toxicity. In ANT1-deficient skeletal muscle, mitochondrial gene expression is induced in association with the hyperproliferation of mitochondria. The ANT1-deficient muscle mitochondria produce excess reactive oxygen species (ROS) and are partially uncoupled. Hence, the muscle respiration under nonphosphorylating conditions is increased. Muscle transcriptome analysis revealed the induction of mitochondrial biogenesis, down-regulation of diabetes-related genes, and increased expression of the genes encoding the myokines FGF21 and GDF15. However, FGF21 was not elevated in serum, and FGF21 and UCP1 mRNAs were not induced in liver or brown adipose tissue (BAT). Hence, increased oxidation of dietary-reducing equivalents by elevated muscle mitochondrial respiration appears to be the mechanism by which ANT1-deficient mice prevent diabetes, demonstrating that the rate of mitochondrial oxidation of calories is important in the etiology of metabolic disease. mitochondria | skeletal muscle | ANT1 | insulin sensitivity

Mitochondrial oxidative stress impairs contractile function but paradoxically increases muscle mass via fibre branching

“…In line with the idea, our m Sod2 KO mice demonstrated mitochondrial proliferation (Figure A–C). An animal model leading to a significant mitochondrial dysfunction (ANT1KO) and compensatory proliferation exhibits redness of the muscle . Another animal model with PGC1‐α overexpression demonstrates increased pigment in skeletal muscle tissues .…”

“…An animal model leading to a significant mitochondrial dysfunction (ANT1KO) and compensatory proliferation exhibits redness of the muscle. 48 Another animal model with PGC1-α overexpression demonstrates increased pigment in skeletal muscle tissues. 49 Increase in muscle mass in gastrocnemius is not caused by a change in fibre size (i.e.…”

Induced in vivo knockdown of the Brca1 gene in skeletal muscle results in skeletal muscle weakness

“…Similar findings have been reported in other animal models where mitochondrial respiration is compromised and associated with reduced specific force capacity that is not a result of muscle atrophy (Gouspillou et al 2018). However, it should be noted that other models demonstrate muscle atrophy accompanied by reduced absolute force with reduced respiration kinetics, although a frequent key characteristic of these models is increased mortality (Diaz et al 2005;Morrow et al 2017). Mitochondrial respiratory dysfunction reported in Brca1KO smi mice was associated with increased Figure 7.…”

The impact of a short-term high-fat diet on mitochondrial respiration, reactive oxygen species production, and dynamics in oxidative and glycolytic skeletal muscles of young rats

“…; Morrow et al. ). Because until recently, T2DM was mainly prevalent in individuals over 50, most of the studies investigating the effects of HFD on mitochondrial function were performed in adult animals.…”

“…Among the underlying mechanisms, fat accumulation in muscle cells were shown to interfere with insulin signaling pathways, and therefore contribute to insulin resistance (Brons and Vaag 2009). Although controversies still remain, the accumulation of mitochondrial dysfunctions, including reactive oxygen species (ROS) over production, impaired energetics, and a reduced ability to oxidize fat, has been proposed to play a major role in this process (Anderson et al 2009;Morrow et al 2017). Because until recently, T2DM was mainly prevalent in individuals over 50, most of the studies investigating the effects of HFD on mitochondrial function were performed in adult animals.…”