Nuclei of aged myofibres undergo structural and functional changes suggesting impairment in RNA processing

Abstract

Advancing adult age is associated with a progressive decrease in skeletal muscle mass, strength and quality known as sarcopenia. The mechanisms underlying age-related skeletal muscle wasting and weakness are manifold and still remain to be fully elucidated. Despite the increasing evidence that the progress of muscle diseases leading to muscle atrophy/dystrophy may be related to defective RNA processing, no data on the morpho-functional features of skeletal muscle nuclei in sarcopenia are available at present. In this view, we have investigated, by combining morphometry and immunocytochemistry at light and electron microscopy, the fine structure of myonuclei as well as the distribution and amount of RNA processing factors in skeletal myofibres of biceps brachii and quadriceps femoris from adult and old rats. Results demonstrate that the myonuclei of aged type II fibres show an increased amount of condensed chromatin and lower amounts of phosphorylated polymerase II and DNA/RNA hybrid molecules, clearly indicating a decrease in pre-mRNA transcription rate compared to adult animals. In addition, myonuclei of aged fibres show decreased amounts of nucleoplasmic splicing factors and an accumulation of cleavage factors, polyadenilated RNA and perichromatin granules, suggesting a reduction in the processing and transport rate of premRNA. During ageing, it seems therefore that in rat myonuclei the entire production chain of mRNA, from synthesis to cytoplasmic export, is less efficient. This failure likely contributes to the reduced responsiveness of muscle cells to anabolic stimuli in the elderly.

Muscle Quality in Aging: a Multi-Dimensional Approach to Muscle Functioning with Applications for Treatment

“…However, resistance training has shown to counteract these changes by enhancing the hormonal response to resistance exercise (i.e., decreased resting cortisol and increase circulating testosterone) [239] and reversing the age-related downregulation of the skeletal muscle IGF-1 system [240], which may promote anabolic potential. Also, within the muscle, age-related alterations in myonuclei may impair hypertrophic capacity [241,242]. Changes in myonuclear content represent a mechanism for modulating protein content and hypertrophy [243][244][245].…”

“…Changes in myonuclear content represent a mechanism for modulating protein content and hypertrophy [243][244][245]. Since myonuclei regulate gene expression and protein synthesis of the surrounding muscle fiber [246], the age-related reduced responsiveness of skeletal muscle may relate to alterations in myonuclear number, distribution, and function [241,242]. Animal models indicate that the myonuclei of aged type II muscle fibers demonstrate a decrease in pre-mRNA transcription, processing, and transport rate compared with younger adult animals [242].…”

“…Since myonuclei regulate gene expression and protein synthesis of the surrounding muscle fiber [246], the age-related reduced responsiveness of skeletal muscle may relate to alterations in myonuclear number, distribution, and function [241,242]. Animal models indicate that the myonuclei of aged type II muscle fibers demonstrate a decrease in pre-mRNA transcription, processing, and transport rate compared with younger adult animals [242]. However, the myonuclear domains of type I and IIa are smaller than in IIb fibers [245], theoretically providing greater potential for proportional hypertrophy within them without exceeding the myonuclear domain.…”

The Prophylactic Role of Vitamin E on the Alternations of Histology and Intermediate Filaments of Aged Rabbit cardiomyocytes

“…Accordingly, the generated free radicals and oxidants are thought to be very significant factors in cardiomyocytes aging. There are factors other than aging which increase oxidative stress by lowering cellular defences and repair mechanisms (Bernhard and Laufer, 2008;Malatesta et al, 2009). The present study demonstrated that after treating the aged rabbits with v itamin E, the cardiac tissue revealed improvement and restoration of the normal structure of the cardiac myofibers with histological appearance nearly similar to the adult group.…”

Muscle stem cells on the edge

“…Furthermore, sarcopenic nuclei largely 26 Cell reprogramming, regeneration and repair lack the large RNP foci that characterize many dystrophies. Still, myonuclei from aged muscle exhibit structural abnormalities consistent with impaired RNA processing [25] as well as aberrant localization of RNA processing factors [26]. Further investigation into these changes, particularly the muscle cell subtypes affected, would help to clarify the role of RNP aggregation/RNA stability in sarcopenia.…”