Mitochondrial uncoupling attenuates sarcopenic obesity by enhancing skeletal muscle mitophagy and quality control

Abstract

Background Sarcopenic obesity is a highly prevalent disease with poor survival and ineffective medical interventions. Mitochondrial dysfunction is purported to be central in the pathogenesis of sarcopenic obesity by impairing both organelle biogenesis and quality control. We have previously identified that a mitochondrial-targeted furazano [3,4-b]pyrazine named BAM15 is orally available and selectively lowers respiratory coupling efficiency and protects against diet-induced obesity in mice. Here, we tested the hypothesis that mitochondrial uncoupling simultaneously attenuates loss of muscle function and weight gain in a mouse model of sarcopenic obesity. Methods Eighty-week-old male C57BL/6J mice with obesity were randomized to 10 weeks of high fat diet (CTRL) or BAM15 (BAM15; 0.1% w/w in high fat diet) treatment. Body weight and food intake were measured weekly. Body composition, muscle function, energy expenditure, locomotor activity, and glucose tolerance were determined after treatment. Skeletal muscle was harvested and evaluated for histology, gene expression, protein signalling, and mitochondrial structure and function. Results BAM15 decreased body weight (54.0 ± 2.0 vs. 42.3 ± 1.3 g, P < 0.001) which was attributable to increased energy expenditure (10.1 ± 0.1 vs. 11.3 ± 0.4 kcal/day, P < 0.001). BAM15 increased muscle mass (52.7 ± 0.4 vs. 59.4 ± 1.0%, P < 0.001), strength (91.1 ± 1.3 vs. 124.9 ± 1.2 g, P < 0.0001), and locomotor activity (347.0 ± 14.4 vs. 432.7 ± 32.0 m, P < 0.001). Improvements in physical function were mediated in part by reductions in skeletal muscle inflammation (interleukin 6 and gp130, both P < 0.05), enhanced mitochondrial function, and improved endoplasmic reticulum homeostasis. Specifically, BAM15 activated mitochondrial quality control (PINK1-ubiquitin binding and LC3II, P < 0.01), increased mitochondrial activity (citrate synthase and complex II activity, all P < 0.05), restricted endoplasmic reticulum (ER) misfolding (decreased oligomer A11 insoluble/soluble ratio, P < 0.0001) while limiting ER stress (decreased PERK signalling, P < 0.0001), apoptotic signalling (decreased cytochrome C release and Caspase-3/9 activation, all P < 0.001), and muscle protein degradation (decreased 14-kDa actin fragment insoluble/soluble ratio, P < 0.001). Conclusions Mitochondrial uncoupling by agents such as BAM15 may mitigate age-related decline in muscle mass and function by molecular and cellular bioenergetic adaptations that confer protection against sarcopenic obesity.

Molecular Mechanisms of Inflammation in Sarcopenia: Diagnosis and Therapeutic Update

“…Earlier this year, the mitochondrial uncoupling agent BAM15 (a protonophore of the respiratory chain) was demonstrated to decrease mitochondrial fission by lowering the expression of Fis1; as a result, increased muscle mass and function, mitochondrial biogenesis quality control, and OXPHOS activity were observed, accompanied by the attenuation of inflammation in sarcopenic mice. These findings provide a new perspective on mitochondrial dynamics in sarcopenia and possible new therapeutical targets [ 73 ].…”

Targeting skeletal muscle mitochondrial health in obesity

“…High-fat diet-fed mice that were treated with 0.1% or 0.15% BAM15 (w/w) exhibited higher whole-body oxygen consumption, had lower RERs, and gained less fat mass compared with untreated mice [ 269 , 270 ], and effects were partly attributable to elevated hepatic lipid oxidation [ 270 ]. Moreover, BAM15 enhanced skeletal muscle mitophagy and mitochondrial content, in old mice fed a HF diet that also exhibited attenuated age-related declines in muscle mass and strength [ 271 ]. Recently, SHC517 was identified as a more potent derivative of BAM15 that was able to prevent diet-induced obesity and improve glucose tolerance in mice [ 272 ].…”

The World Congress of Insulin Resistance, Diabetes and Cardiovascular Disease (WCIRDC)

“…Kirwan reviewed studies of a small molecule mitochondrial uncoupler reducing fat mass and improving insulin sensitivity while increasing muscle mass and function in animal models, offering a potential avenue of approach. 13 …”

“…Kirwan reviewed studies of a small molecule mitochondrial uncoupler reducing fat mass and improving insulin sensitivity while increasing muscle mass and function in animal models, offering a potential avenue of approach. 13 Christos Mantzoros received the Leader in Insulin Resistance Award of the WCIRDC, quoting Homer's introduction to the Odyssey describing "twists and turns [and] far journeys," with research in the complexities of adipose tissue in producing leptin, with deficiencies seen in hypothalamic amenorrhea and in lipodystrophy, 14 in producing follistatin, 15 having autocrine effects on release of follicle-stimulating hormone; on bone, muscle, liver, and in mediating reduction in insulin sensitivity; and in producing the insulin sensitizer adiponectin, 16 which may underlie the benefits of thiazolidinediones.…”

“…Paradoxically, weight loss treatment is typically associated with reduction in muscle mass, potentially lessening the health benefit of intervention. Kirwan reviewed studies of a small molecule mitochondrial uncoupler reducing fat mass and improving insulin sensitivity while increasing muscle mass and function in animal models, offering a potential avenue of approach 13 …”