Facioscapulohumeral muscular dystrophy (FSHD) is a complex genetic disorder resulting in the progressive and selective degeneration of the FSH muscles in adults. Many histopathological features of FSHD mirror muscle aging and loss of regenerative capacity, as evidenced by reduced populations of myogenic progenitors in affected muscles and their defective growth and survival behavior in cell culture. The disease is linked to the contraction of D4Z4 repeats in the subtelomeric region of Chromosome 4, leading to the idea that deletion of these repeats results in the overexpression of adjacently located genes or to Telomere Position effects that lead to telomere shortening and cellular aging. The central hypothesis to be tested in Project 3 is that FSHD is a regenerative disease caused by genetic regulatory disruptions that reduce the viability and/or telomere function in myogenic progenitors, resulting in premature cell aging and consequent loss of muscle regenerative capacity. Immunohistological, cell culture and biomarker approaches will be used to systematically investigate myogenesis in affected and unaffected muscles recovered by surgical biopsy of a large cohort of FSHD patients and first-degree relatives. The goals of these studies are: 1) to identify biomarkers expressed in FSHD muscle and muscle progenitors for monitoring the efficacy of FSHD clinical trials;2) to identify disease-specific biomarkers that have functional roles in FSHD muscle pathology as targets for development of drugs, RNAi, and cell-based therapeutics that promote satellite cell survival, myogenesis and improved muscle regeneration;and 3) to establish validated cell and mouse models of FSHD. Biomarker and telomere studies will enable investigations of the underlying molecular pathology of FSHD to test D4Z4 locus control and telomere position effect (TPE) disease mechanisms. Project 3 benefits from the distinct multidisciplinary expertise of Center investigators and collaborators working in an interactive research environment and from the exceptional resources and technical support of the Cell Core with its unique collection of FSHD muscle biopsies and muscle cell cultures. The proposed studies will elucidate the disease role of myogenesis and muscle regeneration in FSHD and provide validated cell models for investigations of FSHD disease mechanisms and the development of drug and cell-based therapeutics for the treatment of FSHD, a currently untreatable disease.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Specialized Center--Cooperative Agreements (U54)
Project #
Application #
Study Section
Special Emphasis Panel (ZAR1-KM-J)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Boston Biomedical Research Institute
United States
Zip Code
Sakellariou, Paraskevi; O'Neill, Andrea; Mueller, Amber L et al. (2016) Neuromuscular electrical stimulation promotes development in mice of mature human muscle from immortalized human myoblasts. Skelet Muscle 6:4
Chen, Jennifer Cj; King, Oliver D; Zhang, Yuanfan et al. (2016) Morpholino-mediated Knockdown of DUX4 Toward Facioscapulohumeral Muscular Dystrophy Therapeutics. Mol Ther 24:1405-11
Henninger, Nils; Bouley, James; Sikoglu, Elif M et al. (2016) Attenuated traumatic axonal injury and improved functional outcome after traumatic brain injury in mice lacking Sarm1. Brain 139:1094-105
Jones, Takako I; King, Oliver D; Himeda, Charis L et al. (2015) Individual epigenetic status of the pathogenic D4Z4 macrosatellite correlates with disease in facioscapulohumeral muscular dystrophy. Clin Epigenetics 7:37
Homma, Sachiko; Beermann, Mary Lou; Boyce, Frederick M et al. (2015) Expression of FSHD-related DUX4-FL alters proteostasis and induces TDP-43 aggregation. Ann Clin Transl Neurol 2:151-66
Moyer, Adam L; Wagner, Kathryn R (2015) Mammalian Mss51 is a skeletal muscle-specific gene modulating cellular metabolism. J Neuromuscul Dis 2:371-385
Huh, Yang Hoon; Noh, Minsoo; Burden, Frank R et al. (2015) Sparse feature selection identifies H2A.Z as a novel, pattern-specific biomarker for asymmetrically self-renewing distributed stem cells. Stem Cell Res 14:144-54
Lek, Angela; Rahimov, Fedik; Jones, Peter L et al. (2015) Emerging preclinical animal models for FSHD. Trends Mol Med 21:295-306
Zhang, Yuanfan; King, Oliver D; Rahimov, Fedik et al. (2014) Human skeletal muscle xenograft as a new preclinical model for muscle disorders. Hum Mol Genet 23:3180-8
Jones, Takako I; Yan, Chi; Sapp, Peter C et al. (2014) Identifying diagnostic DNA methylation profiles for facioscapulohumeral muscular dystrophy in blood and saliva using bisulfite sequencing. Clin Epigenetics 6:23

Showing the most recent 10 out of 23 publications