calpain and Weight-Loss

Loss of muscle mass and force with age leads to fall risk, mobility impairment, and reduced quality of life. This article shows that BDA-410, a calpain inhibitor, induced loss of body weight and fat but not lean mass or skeletal muscle proteins in a cohort of sedentary 23-month-old mice. Food and water intake and locomotor activity were not modified, whereas BDA-410 treatment decreased intramyocellular lipid and perigonadal fat, increased serum nonesterified fatty acids, and upregulated the genes mediating lipolysis and oxidation, lean phenotype, muscle contraction, muscle transcription regulation, and oxidative stress response. This finding is consistent with our recent report that lipid accumulation in skeletal myofibers is significantly correlated with slower fiber-contraction kinetics and diminished power in obese older adult mice. A proteomic analysis and immunoblot showed downregulation of the phosphatase PPP1R12B, which increases phosphorylated myosin half-life and modulates the calcium sensitivity of the contractile apparatus. This study demonstrates that BDA-410 exerts a beneficial effect on skeletal muscle contractility through new, alternative mechanisms, including enhanced lipolysis, upregulation of "lean phenotype-related genes," downregulation of the PP1R12B phosphatase, and enhanced excitation-contraction coupling. This single compound holds promise for treating age-dependent decline in muscle composition and strength.

Topics: Animals; Calpain; Down-Regulation; Lipolysis; Mice; Muscle, Skeletal; Pharmacogenetics; Physical Conditioning, Animal; Protein Phosphatase 1; Sulfonamides; Treatment Outcome; Weight Loss

The influence of cancer on skeletal muscle calpain expression and activity in humans is poorly understood. We tested the hypothesis that calpain activity is increased in skeletal muscle from gastric cancer patients with no or <5% weight loss. Muscle biopsies were obtained from rectus abdominis muscle in 15 patients who underwent surgery for gastric cancer and had <5% weight loss and also in 15 control patients. Calpain activity was determined using a calpain-specific substrate in the absence or presence of calcium. The expression of μ- and m-calpain, calpastatin, atrogin-1, and MuRF1 was determined by real-time polymerase chain reaction. Calpain activity was increased by 70% in cancer patients compared with controls. There were no differences in mRNA levels for μ- and m-calpain, calpastatin, atrogin-1, or MuRF1 between control and cancer patients. Calpain activity may be increased in muscle from gastric cancer patients even before changes in molecular markers of muscle wasting and significant weight loss occur.

Topics: Adenocarcinoma; Aged; Calpain; Enzyme Activation; Female; Humans; Male; Middle Aged; Muscle, Skeletal; Proteasome Endopeptidase Complex; RNA, Messenger; Signal Transduction; Stomach Neoplasms; Ubiquitin; Weight Loss