Biology subjects

Robertson, R.

Publications and source records attributed to Robertson, R..

3 recordsLinked to original sources

bioRxiv2026

Phosphorylation of CARM1 at Ser572 preserves muscle stem cell self-renewal by restricting premature myogenic commitment

Skeletal muscle regeneration depends on satellite cells, which must balance myogenic commitment with self-renewal to maintain regenerative capacity throughout life. The methyltransferase CARM1 is a key regulator of satellite cell fate, acting through methylation of PAX7 to promote Myf5 expression and myogenic commitment. The dystrophin glycoprotein complex regulates this pathway through p38{gamma}-mediated phosphorylation of CARM1 at Ser572, however the physiological role of this phosphorylation event in vivo remains unknown. Here, we generated a phosphorylation-deficient CARM1 knock-in mouse (CARM1 SA) to determine how CARM1 Ser572 phosphorylation regulates satellite cell fate during regenerative myogenesis. Satellite cell-derived myoblasts from CARM1 SA mice exhibited reduced PAX7 expression, impaired fusion, and abnormal myotube formation despite transcriptional signatures consistent with accelerated myogenic progression. Ex vivo single-myofiber assays revealed precocious acquisition of a committed progenitor identity accompanied by a reduction in the self-renewing satellite cell population. While muscle development and regeneration following a single injury were largely preserved, repeated regenerative challenge resulted in progressive depletion of the satellite cell pool in CARM1 SA mice. Transcriptomic analysis demonstrated minimal effects under homeostatic conditions but identified substantial alterations during regeneration, including reduced expression of extracellular matrix-associated genes, impaired TGF{beta}-SMAD signaling, decreased Tgfbr3 expression, and increased MYC activity, consistent with a loss of self-renewal programs and enhanced activation. Collectively, these findings demonstrate that phosphorylation of CARM1 at Ser572 is a critical mechanism to delay satellite cell commitment, thereby maintaining a balance between self-renewal and commitment to ensure long-term maintenance of the muscle stem cell compartment.

cell biology↗

bioRxiv2024

Satellite stem cell dysfunction in Duchenne muscular dystrophy

Satellite cells are muscle-resident stem cells that maintain and repair muscle. Increasing evidence supports the contributing role of satellite cells in Duchenne muscular dystrophy (DMD), a lethal degenerative muscle disease caused by loss of dystrophin. However, whether or not satellite cells exhibit dysfunction due to loss of dystrophin remains unresolved. Here, we used single cell RNA-sequencing (scRNA-seq) to determine how dystrophin deficiency impacts the satellite cell transcriptome and cellular composition by comparing satellite cells from mdx and the more severe D2-mdx DMD mouse models. DMD satellite cells were disproportionally found within myogenic progenitor clusters and a previously uncharacterized DMD enriched cluster. Despite exposure to different dystrophic environments, mdx and D2-mdx satellite cells exhibited overlapping dysregulation in gene expression and associated biological pathways. When comparing satellite stem cell versus myogenic progenitor populations, we identified unique dysfunctions between DMD and healthy satellite cells including apoptotic cell death and senescence, respectively. Pseudotime analyses revealed differences in cell fate trajectories indicating that DMD satellite cells are stalled in their differentiation capacity. In vivo regeneration assays confirmed that DMD satellite cells exhibit impaired myogenic gene expression and cell fate dynamics during regenerative myogenesis. These defects in differentiation capacity are accompanied by impaired senescence and autophagy dynamics. Finally, we demonstrate that inducing autophagy can rescue differentiation of DMD progenitors. Our findings provide novel molecular evidence of satellite cell dysfunction in DMD, expanding on our understanding of their role in its pathology and suggesting pathways to target and enhance their regenerative capacity.

cell biology↗

bioRxiv2021

Age-related changes in Tau and Autophagy in human brain in the absence of neurodegeneration

Tau becomes abnormally hyper-phosphorylated and aggregated in tauopathies like Alzheimers disease (AD). As age is the greatest risk factor for developing AD, it is important to understand how tau protein itself, and the pathways implicated in its turnover, change during aging. We investigated age-related changes in total and phosphorylated tau in brain samples from two cohorts of cognitively normal individuals spanning 19-74 years, without overt neurodegeneration. One cohort utilised resected tissue and the other used post-mortem tissue. Total soluble tau levels declined with age in both cohorts. Phosphorylated tau was undetectable in the post-mortem tissue but was clearly evident in the resected tissue and did not undergo significant age-related change. To ascertain if the decline in soluble tau was correlated with age-related changes in autophagy, three markers of autophagy were tested but only two appeared to increase with age and the third was unchanged. This implies that in individuals who do not develop neurodegeneration, there is an age-related reduction in soluble tau which could potentially be due to age-related changes in autophagy. Thus, to explore how an age-related increase in autophagy might influence tau-mediated dysfunctions in vivo, autophagy was enhanced in a Drosophila model and all age-related tau phenotypes were significantly ameliorated. These data shed light on age-related physiological changes in proteins implicated in AD and highlights the need to study pathways that may be responsible for these changes. It also demonstrates the therapeutic potential of interventions that upregulate turnover of aggregate-prone proteins during aging.

neuroscience↗