Progeria is caused by a mutation in Lamin A (LMNA), a gene that codes for a vital component of cellular structure. The cells of progeria patients are misshaped and dysfunctional, leading to symptoms that appear superficially similar to highly accelerated aging. One of the outcomes of this discovery is a broadening of research into lamin proteins in normal aging; researchers have found low levels of malformed lamins and related proteins in older individuals. Evidence is accumulating for the presence of these proteins to contribute to aspects of aging, but the size of the effect is still very much in question. It may or may not be significant in comparison to, say, the harms caused by the various forms of molecular damage outlined in the SENS rejuvenation research programs. The open access paper here delves into an association between lamins and muscle cells, drawing a potential connection to the loss of muscle mass and strength that occurs with age, a condition called sarcopenia.
Biological aging involves complex dysfunctional cellular processes with unclear underlying mechanisms, including a potential involvement of alterations at the nuclear level in a wide range of tissues. Normal nuclear function requires lamin A, a protein located at the inner nuclear envelope, where it regulates nuclear integrity, architecture, and chromatin organization. Defective processing of lamin A and accumulation of its precursors, progerin and/or prelamin A, occurs during physiological aging and is also responsible for premature aging syndromes. Symptoms include growth impairment, bone and skin abnormalities, joint contractures, and muscle dysfunction. In the present study, we aimed to determine whether and how high levels of prelamin A deteriorate the function of skeletal muscle fibers.
Myofibers contain several hundred peripherally located nuclei. Each of them controls protein synthesis in a defined volume of cytoplasm termed the myonuclear domain (MND). Regular positioning of these nuclei is essential for optimal nuclear cooperation, MND size, and efficient regulation and distribution of gene products. Here, we tested the hypothesis that an accumulation of prelamin A would alter nuclear number and positioning, ultimately disrupting the ability of fibers to generate force. To test this, we used various transgenic mouse models that mimic premature aging syndromes, wherein the composition of nuclear envelope proteins is altered. We isolated and membrane-permeabilized individual muscle fibers, then ran a series of contractile and morphological analyses, including an evaluation of the 3D organization of nuclei.
Our results indicate that, in the presence of prelamin A, the abundance of nuclei and myosin content is markedly reduced within muscle fibers. This leads to a concept by which the remaining myonuclei are very distant from each other and are pushed to function beyond their maximum cytoplasmic capacity, ultimately inducing muscle fiber weakness.