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Mitochondrial Uncoupling Reverses Sarcopenic Obesity while Enhancing Glucose Homeostasis and Muscle Function in Aged C57BL/6J Mice
Author(s) -
Axelrod Christopher,
Dantas Wagner,
King William,
Zunica Elizabeth,
Kirwan John
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.02305
Subject(s) - sarcopenic obesity , homeostasis , glucose homeostasis , function (biology) , medicine , sarcopenia , endocrinology , obesity , chemistry , microbiology and biotechnology , biology , insulin resistance
Obesity exacerbates the age‐related decline in muscle function and metabolic health. Despite this, medical treatments for sarcopenic obesity remain limited to lifestyle and behavioral modifications such as calorie restriction and exercise. Here, we hypothesized that sarcopenic obesity can be effectively reversed by reducing mitochondrial bioenergetic efficiency. To achieve this, 80‐week‐old male C57BL/6J mice with obesity were randomized to 10 weeks of either vehicle (V) or BAM15 (B; 0.1% w/w in diet) treatment, an orally available mitochondrial uncoupler. Body weight and food intake were measured weekly. Body composition, muscle function, energy expenditure, locomotor activity, and glucose tolerance were determined after treatment. Blood and organ weights were obtained at necropsy. BAM15 reduced body weight (B:42.3±1.3 vs. V:54.0±1.3 g, P=0.002) by increasing energy expenditure (B:0.012±0.0 vs. V:0.010±0.0 kcal/g/hr, P=0.003) without altering food intake (B:0.67±0.07 vs. V:0.63±0.02 kcal/hr, P=0.58). BAM15 reduced body fat (B:21.3±1.6 vs. V:31.4±0.5%, P=0.0001) while preserving lean mass (B:59.4±1.0 vs. V:52.7±0.4%, P=0.034). BAM15 increased both muscle strength (B:128.0±2.5 vs. V:92.0±2.0 g, P<0.0001) and locomotor activity (B:432.7±32.0vs. V:347.0±14.4 m/hr, P=0.035). Additionally, BAM15 reduced circulating glucose (B:202.7±9.3 vs. V:245.0±6.4 mg/dL, P=0.004), C‐peptide (B:0.68±0.09 vs. V:1.60±0.22 mg/dL, P=0.004), and insulin concentrations (B:1.5±0.2 vs. V:2.6±0.3 ng/mL, P=0.02) while modestly improving glucose tolerance (B:236.8±13.1 vs. V:310.0±15.6 2‐hr mg/dL, P=0.03). Taken together, these data indicate that reducing mitochondrial coupling efficiency protects against age‐related decline in muscle function while improving peripheral metabolic health.