title: Calpain inhibition rescues troponin T3 fragmentation, increases Cav1.1, and enhances skeletal muscle force in aging sedentary mice.
abstract: Loss of strength in human and animal models of aging can be partially attributed to a well-recognized decrease in muscle mass; however, starting at middle-age, the normalized force (force/muscle cross-sectional area) in the knee extensors and single muscle fibers declines in a curvilinear manner. Strength is lost faster than muscle mass and is a more consistent risk factor for disability and death. Reduced expression of the voltage sensor Ca(2+) channel α1 subunit (Cav1.1) with aging leads to excitation-contraction uncoupling, which accounts for a significant fraction of the decrease in skeletal muscle function. We recently reported that in addition to its classical cytoplasmic location, fast skeletal muscle troponin T3 (TnT3) is fragmented in aging mice, and both full-length TnT3 (FL-TnT3) and its carboxyl-terminal (CT-TnT3) fragment shuttle to the nucleus. Here, we demonstrate that it regulates transcription of Cacna1s, the gene encoding Cav1.1. Knocking down TnT3 in vivo downregulated Cav1.1. TnT3 downregulation or overexpression decreased or increased, respectively, Cacna1s promoter activity, and the effect was ablated by truncating the TnT3 nuclear localization sequence. Further, we mapped the Cacna1s promoter region and established the consensus sequence for TnT3 binding to Cacna1s promoter. Systemic administration of BDA-410, a specific calpain inhibitor, prevented TnT3 fragmentation, and Cacna1s and Cav1.1 downregulation and improved muscle force generation in sedentary old mice.
authors.affiliation: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.|Molecular Medicine and Translational Science, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Tan
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Pereyra
authors.affiliation: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Zhong-Min
authors.initials: ZM
authors.lastname: Wang
authors.affiliation: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Alexander
authors.initials: A
authors.lastname: Birbrair
authors.affiliation: Molecular Medicine and Translational Science, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Reisz
authors.affiliation: Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Daniel Clark
authors.initials: DC
authors.lastname: Files
authors.affiliation: Pulmonary, Critical Care, Allergy and Immunologic Diseases, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Lina
authors.initials: L
authors.lastname: Purcell
authors.affiliation: Department of Otolaryngology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Xin
authors.initials: X
authors.lastname: Feng
authors.affiliation: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Maria L
authors.initials: ML
authors.lastname: Messi
authors.affiliation: Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Hanzhong
authors.initials: H
authors.lastname: Feng
authors.affiliation: Department of Biochemistry and Molecular Biology, Brody School of Medicine, East Carolina University, Greenville, NC, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Chalovich
authors.affiliation: Wayne State University School of Medicine, Detroit, MI, USA.
authors.forename: Jian-Ping
authors.initials: JP
authors.lastname: Jin
authors.affiliation: Molecular Medicine and Translational Science, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Cristina
authors.initials: C
authors.lastname: Furdui
authors.affiliation: Department of Internal Medicine, Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA.|J Paul Sticht Center on Aging, Wake Forest School of Medicine, Winston-Salem, NC, USA.
authors.forename: Osvaldo
authors.initials: O
authors.lastname: Delbono
mesh_terms: D000375:Aging / Q000502:physiology*; D000818:Animals; D001696:Biomechanical Phenomena / Q000187:drug effects; D020746:Calcium Channels, L-Type / Q000235:genetics / Q000378:metabolism*; D002154:Calpain / Q000037:antagonists & inhibitors* / Q000378:metabolism; D002460:Cell Line; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D055785:Gene Knockdown Techniques; D007537:Isometric Contraction / Q000187:drug effects; D008810:Mice, Inbred C57BL; D018763:Muscle Fatigue / Q000187:drug effects; D018656:Muscle Fibers, Fast-Twitch / Q000187:drug effects / Q000502:physiology; D018657:Muscle Fibers, Slow-Twitch / Q000187:drug effects / Q000502:physiology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000201:enzymology* / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D020107:Troponin T / Q000378:metabolism*
chemical_list: C529218:CACNA1S protein, mouse; D020746:Calcium Channels, L-Type; C572617:N-1-(hydroxy(3-oxo-2-phenyl-1-cyclopropen-1-yl)methyl)-2-methylpropyl-2-benzenesulfonylamino-4-methylpentanamide; D013449:Sulfonamides; D020107:Troponin T; D002154:Calpain
keywords: aging; calcium channel; calpain; excitation-contraction coupling; skeletal muscle; troponin T