Svensson, R. B. | bioRxiv Science

bioRxiv2024

Muscle Fibroblasts and Stem Cells Stimulate Motor Neurons in An Age and Exercise-Dependent Manner

Exercise preserves neuromuscular function in ageing through unknown mechanisms. Skeletal muscle fibroblasts (FIB) and stem cells (MuSC) are abundant in skeletal muscle and reside close to neuromuscular junctions, but their relative roles in motor neuron maintenance remain undescribed. Using direct co-cultures of embryonic rat motor neurons with either human MuSC or FIB, RNA sequencing revealed profound differential regulation of the motor neuron transcriptome, with FIB generally favoring neuron growth and cell migration and MuSC favoring production of ribosomes and translational machinery. Conditioned medium from FIB was superior to MuSC in preserving motor neurons and increasing their maturity. Lastly, we established the importance of donor age and exercise status and found an age-related distortion of motor neuron and muscle cell interaction that was fully mitigated by lifelong physical activity. In conclusion, we show that human muscle FIB and MuSC synergistically stimulate the growth and viability of motor neurons, which is further amplified by regular exercise.

physiology↗

bioRxiv2023

Marked irregular myofiber shape is a hallmark of human skeletal muscle aging and is reversed by heavy resistance training

BackgroundAge-related loss of strength is disproportionally greater than the loss of mass, suggesting maladaptations in the neuro-myo-tendinous system. Myofibers are often misshaped in aged and diseased muscle, but systematic analyses of large sample sets are lacking. Our aim was to investigate myofiber shape in relation to age, exercise, myofiber type, species, and sex. MethodsPreviously collected vastus lateralis muscle biopsies (n=265) from 197 males and females, covering an age-span of 20 to 97 years, were examined. The gastrocnemius and soleus muscles of 7 C57BL/6 mice were also examined. Immunofluorescence and ATPase stainings of muscle cross-sections were used to measure myofiber cross-sectional area (CSA) and perimeter, from which a shape factor index (SFI) was calculated in a fiber type specific manner (type I and II in humans; type I, IIa, IIx and IIb in mice). Heavy resistance training (RT) was performed 3 times per week for 3-4 months by a subgroup (n=59). Correlation analyses were performed comparing SFI and CSA with age, muscle mass, maximal voluntary contraction (MVC), rate of force development (RFD), and specific force (MVC/muscle mass). ResultsIn human muscle, SFI was positively correlated with age for both type I (R2=0.20) and type II (R2=0.38) myofibers. When subjects were separated into age cohorts, SFI was lower for type I (p<0.001) and II (p<0.001) myofibers in Young (20-36) compared to Old (60-80), and higher for type I (p<0.05) and II (p<0.001) myofibers in the Oldest Old (>80) compared to Old. The increased SFI in old muscle was observed in myofibers of all sizes. Within all three age cohorts, type II myofibers SFI was higher than for type I myofibers (p<0.001), which was also the case in mice muscles (p<0.001). Across age cohorts, there was no difference between males and females in SFI for either type I (p=0.496/0.734) or II (p=0.176/0.585) myofibers. Multiple linear regression revealed that SFI, after adjusting for age and myofiber CSA, has independent explanatory power for 8 out of 10 indices of muscle mass and function. RT reduced SFI of type II myofibers in both Young and Old (p<0.001). ConclusionsHere, we identify type I and II myofiber shape in humans and mice as a hallmark of muscle ageing, that independently predicts volumetric and functional assessments of muscle health. RT reverts the shape of type II myofibers, indicating that lack of neuromuscular activation might lead to myofiber deformity.

physiology↗