Biology subjects

Joseph, L. C.

Publications and source records attributed to Joseph, L. C..

3 recordsLinked to original sources

bioRxiv2026

Lamin A/C depletion from myofibers and satellite cells in mice reveals selective muscle pathology

Mutations in the laminA/C gene (LMNA), which encodes the nuclear lamina proteins lamin A and lamin C (lamin A/C), have been linked to different human diseases affecting different tissues. Most LMNA mutations cause cardiomyopathy and muscular dystrophy, such as autosomal dominant Emery-Dreifuss muscular dystrophy. Recent studies to understand striated muscle laminopathies have taken advantage of Lmna conditional knockout mice to examine the effects of lamin A/C depletion in cardiomyocytes and cardiac fibroblasts. However, the role of lamin A/C in skeletal muscle has largely been uncharacterized using conditional knockout mice. We used different mouse lines to deplete lamin A/C from specific cell types in striated muscle. Lamin A/C depletion from fetal myofibers and cardiomyocytes led to no observable phenotype in the skeletal muscles despite leading to dramatic heart dilation and early lethality. Depletion of lamin A/C from both skeletal myofibers and satellite cells was lethal, with the most dramatic myopathic abnormalities observed in the intrinsic muscles of the tongue. The presence of lamin A/C in skeletal muscle satellite cells prevented the development of lethal myopathy when the proteins were deleted only from differentiated myofibers. Overall, our results provide a foundation for understanding the roles of lamin A/C in muscle maintenance and development, including the variable skeletal muscle involvement and much more invariant cardiomyopathy in patients with LMNA mutations.

pathology↗

bioRxiv2025

Prelamin A Does Not Promote Atherosclerosis or Vascular Smooth Muscle Loss

BACKGROUNDHutchinson-Gilford progeria syndrome (HGPS) is an accelerated aging disorder characterized by numerous symptoms, including early-onset atherosclerosis, with most patients suffering fatal myocardial infarctions or strokes by the second decade of life. HGPS is caused by mutations in LMNA that lead to expression of an internally truncated, farnesylated prelamin A variant called progerin, which induces loss of vascular smooth muscle cells (VSMCs). Some studies have also reported that accumulation of full-length farnesylated prelamin A, which is normally completely processed to mature non-farnesylated lamin A, can also drive vascular pathology during physiological aging. METHODSTo assess the effects of prelamin A expression on atherosclerosis and aortic VSMCs, we used LmnaL648R/L648R mice that express a prelamin A variant with a lysine to arginine point mutation that prevents its processing to mature lamin A. To determine if prelamin A expression has an impact on atherosclerotic plaques, we crossed LmnaL648R/L648R mice to LDL receptor-deficient Ldlr-/- mice that develop hyperlipidemia on a high-fat diet. RESULTSAtherosclerotic plaque lesion area and necrotic core area were not different in hyperlipidemic LmnaL648R/L648R mice that expressed only prelamin A, and no mature lamin A, compared to hyperlipidemic Lmna+/+ mice that expressed only fully-processed mature lamin A and no prelamin A. Additionally, exclusive prelamin A expression did not result in loss of aortic VSMCs or adventitial thickening in hyperlipidemic LmnaL648R/L648R mice with atherosclerosis at 28 weeks of age. Indeed, aortic vascular smooth muscle remained normal in older LmnaL648R/L648R mice at 52 weeks of age. CONCLUSIONSIn contrast to the prelamin A variant progerin expressed in HGPS, prelamin A does not appear to cause vascular smooth muscle loss, promote atherosclerosis or drive vascular aging.

molecular biology↗

bioRxiv2025

The nucleus activates mechano-responsiveness via FHOD-associated LINC complexes

The nucleus is the defining organelle of eukaryotic cells. It is usually considered a target organelle for cellular inputs. Here, we find that the nucleus is not simply a "passive" responder, but an active organelle directing the mechanical properties of the actin cytoskeleton it engages. Biochemically, interaction of FHOD formins with nesprin-2 of the nuclear LINC complex activates their actin bundling activity making them more potent than known bundlers like fascin or -actinin. In cells, FHOD-associated LINC complexes enhance the mechanical resistance of nuclear-engaged actin cables in polarizing fibroblasts and sarcomeres in developing cardiomyocytes. Hypertrophic cardiomyopathy-associated variants of FHOD3 are defective in these processes. In mice, the FHOD3 R637P disease-causing allele results in embryonic lethality when homozygous and in stress-induced cardiac hypertrophy when heterozygous. These results show that the nucleus actively directs its mechanical environment and that disruption of this capability in heart leads to cardiac hypertrophy.

cell biology↗