Histone deacetylase 4 protects from denervation and skeletal muscle atrophy in a murine model of amyotrophic lateral sclerosis

Background: Histone deacetylase 4 (HDAC4) has been proposed as a target for Amyotrophic Lateral Sclerosis (ALS) because it mediates nerve-skeletal muscle interaction and since its expression in skeletal muscle correlates with the severity of the disease. However, our recent studies on the skeletal muscle response upon long-term denervation highlighted the importance of HDAC4 in maintaining muscle integrity. Methods: To fully identify the yet uncharacterized HDAC4 functions in ALS, we genetically deleted HDAC4 in skeletal muscles of a mouse model of ALS. Body weight, skeletal muscle, innervation and spinal cord were analyzed over time by morphological and molecular analyses. Transcriptome analysis was also performed to delineate the signaling modulated by HDAC4 in skeletal muscle of a mouse model of ALS. Findings: HDAC4 deletion in skeletal muscle caused earlier ALS onset, characterized by body weight loss, muscle denervation and atrophy, and compromised muscle performance, although the main catabolic pathways were not activated. Transcriptome analysis identified the gene networks modulated by HDAC4 in ALS, revealing UCP1 as a top regulator that may be implicated in worsening ALS features. Interpretation: HDAC4 plays an important role in preserving innervations and skeletal muscle in ALS, likely by modulating the UCP1 gene network. Our study highlights a possible risk in considering HDAC inhibitors for the treatment of ALS. Fund: This work was supported by FIRB grant (RBFR12BUMH) from Ministry of Education, Universities and Research, by Fondazione Veronesi, by Sapienza research project 2017 (RM11715C78539BD8) and Polish National Science Center grant (UMO-2016/21/B/NZ3/03638)

The ecological impact of conquest and colonization on a medieval frontier landscape: combined palynological and geochemical analysis of lake sediments from Radzyń Chełminski, northern Poland

Slavic and German colonization of the southern Baltic between the 8th and 15th centuries A.D. is well-documented archaeologically and historically. Despite the large number of pollen profiles from Poland, few palaeoecological studies have examined the ecological impact of a process that was central to the expansion of European, Christian, societies. This study aims to redress this balance through multiproxy analysis of lake sediments from Radzyń Chełminski, Northern Poland, using pollen, element geochemistry (Inductively Coupled-Optical Emission Spectroscopy [ICP-OES]), organic content, and magnetic susceptibility. The close association between lake and medieval settlements presents the ideal opportunity to reconstruct past vegetation and land-use dynamics within a well-documented archaeological, historical, and cultural context. Three broad phases of increasing landscape impact are visible in the pollen and geochemical data dating from the 8th/9th, 10th/11th, and 13th centuries, reflecting successive phases of Slavic and German colonization. This involved the progressive clearance of oak-hornbeam dominated woodland and the development of an increasingly open agricultural landscape. Although the castles and towns of the Teutonic Order remain the most visible signs of medieval colonization, the palynological and geochemical data demonstrate that the major phase of woodland impact occurred during the preceding phase of Slavic expansion; Germans colonists were entering a landscape already significantly altered