title: BDA-410 Treatment Reduces Body Weight and Fat Content by Enhancing Lipolysis in Sedentary Senescent Mice.
abstract: 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.
authors: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.|Biochemistry Research Institute of La Plata (INIBIOLP)/CONICET, School of Medicine, National University of La Plata, Buenos Aires, Argentina.
authors: Andrea S
authors: AS
authors: Pereyra
authors: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors: Zhong-Min
authors: ZM
authors: Wang
authors: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors: Maria Laura
authors: ML
authors: Messi
authors: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.|J Paul Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors: Tan
authors: T
authors: Zhang
authors: Molecular Medicine and Translational Science.
authors: Hanzhi
authors: H
authors: Wu
authors: Department of Neurobiology and Anatomy.|Department of Pathology, Section on Comparative Medicine.
authors: Thomas C
authors: TC
authors: Register
authors: Department of Neurobiology and Anatomy.
authors: Elizabeth
authors: E
authors: Forbes
authors: Molecular Medicine and Translational Science.
authors: Nelmi O
authors: NO
authors: Devarie-Baez
authors: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.|Pulmonary and Critical Care Allergy and Immunology, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors: Daniel Clark
authors: DC
authors: Files
authors: Basic and Applied Immunological Research Center (CINIBA), School of Medicine, Universidad Nacional de La Plata, Buenos Aires, Argentina.
authors: Martin C
authors: MC
authors: Abba
authors: Molecular Medicine and Translational Science.
authors: Cristina
authors: C
authors: Furdui
authors: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina.|J Paul Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, North Carolina.
authors: Osvaldo
authors: O
authors: Delbono
mesh_terms: D000818:Animals; D002154:Calpain / Q000037:antagonists & inhibitors / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D008066:Lipolysis / Q000187:drug effects / Q000502:physiology; D051379:Mice; D018482:Muscle, Skeletal / Q000187:drug effects / Q000502:physiology; D010597:Pharmacogenetics; D010805:Physical Conditioning, Animal / Q000502:physiology; D054645:Protein Phosphatase 1 / Q000235:genetics / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology*; D016896:Treatment Outcome; D015431:Weight Loss / Q000187:drug effects / Q000502:physiology
chemical_list: C572617:N-1-(hydroxy(3-oxo-2-phenyl-1-cyclopropen-1-yl)methyl)-2-methylpropyl-2-benzenesulfonylamino-4-methylpentanamide; D013449:Sulfonamides; D054645:Protein Phosphatase 1; D002154:Calpain
keywords: Aging; Body fat; Calpain; Sarcopenia; Skeletal muscle