Biology subjects

Kjaer, M.

Publications and source records attributed to Kjaer, M..

4 recordsLinked to original sources

bioRxiv2024

Fibre type differences in the organisation of mononuclear cells and myonuclei at the tips of human myofibres

The myotendinous junction (MTJ) is a weak link in the musculoskeletal system. Here, we isolated the tips of single myofibres from healthy human hamstring muscles for confocal microscopy (n=6) and RNAscope in situ hybridization (n=6) to gain insight into the profiles of cells and myonuclei in this region. A marked presence of mononuclear cells was observed coating the fibre tips, with a median of 29 (range 16-63) and 16 (9-23) cells per fibre for type I and II myofibres, respectively (p<0.05). The number and density of myonuclei gradually increased from the myofibre proper towards the tip (p<0.05), similarly for both fibre types, and a greater number of COL22A1-expressing nuclei was seen in type II vs type I myofibres (p<0.05). These divergent fibre type-specific characteristics of the MTJ reflect the respective demands for remodelling of the tendon and myofibre sides of the junction according to loading patterns. This insight refines our fundamental understanding of the human MTJ at the cell and structural levels. Summary statementAt the site of attachment to tendon, type I and II human myofibre tips display divergent numbers of mononuclear cells and COL22A1+ nuclei, changing our understanding of myotendinous junction biology.

physiology↗

bioRxiv2023

The mitochondrial mRNA stabilizing protein, SLIRP, regulates skeletal muscle mitochondrial structure and respiration by exercise-recoverable mechanisms

Summary and graphical abstractDecline in mitochondrial function associates with decreased muscle mass and strength in multiple conditions, including sarcopenia and type 2 diabetes. Optimal treatment could include improving mitochondrial function, however, there are limited and equivocal data regarding the molecular cues controlling muscle mitochondrial plasticity. Here we uncover the mitochondrial-mRNA-stabilizing protein SLIRP, in complex with LRPPRC, as a PGC-1 target that regulates mitochondrial structure, respiration, and mitochondrially-encoded-mRNA pools in skeletal muscle. Exercise training effectively counteracted mitochondrial defects induced by loss of LRPPRC/SLIRP, despite sustained low mitochondrially-encoded-mRNA pools, via increased mitoribosome translation capacity. In humans, exercise training robustly increased muscle SLIRP and LRPPRC protein content across exercise modalities and sexes, yet this increase was less prominent in subjects with type 2 diabetes. Our work identifies a mechanism of post-transcriptional mitochondrial regulation in skeletal muscle through mitochondrial mRNA stabilization. It emphasizes exercise as an effective approach to alleviate mitochondrial defects by possibly increasing mitoribosome capacity. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=142 SRC="FIGDIR/small/564600v2_ufig1.gif" ALT="Figure 1"> View larger version (61K): org.highwire.dtl.DTLVardef@1cdc6c5org.highwire.dtl.DTLVardef@b4cb1borg.highwire.dtl.DTLVardef@182871corg.highwire.dtl.DTLVardef@7462ea_HPS_FORMAT_FIGEXP M_FIG C_FIG

molecular biology↗

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↗

bioRxiv2022

Distinct myofibre domains of the human myotendinous junction revealed by single nucleus RNA-seq

The myotendinous junction (MTJ) is a specialized domain of the multinucleated myofibre, faced with the challenge of maintaining robust cell-matrix contact with the tendon under high mechanical stress and strain. Here, we profiled 24,161 nuclei in semitendinosus muscle-tendon samples from 3 healthy males by single nucleus RNA-sequencing (snRNA-seq), alongside spatial transcriptomics, to gain insight into the genes characterizing this specialization in humans. We identified a cluster of MTJ myonuclei, represented by 47 enriched transcripts, of which the presence of ABI3BP, ABLIM1, ADAMTSL1, BICD1, CPM, FHOD3, FRAS1 and FREM2 was confirmed at the MTJ at the protein level by immunofluorescence. Four distinct subclusters of MTJ myonuclei were apparent and segregated into two COL22A1-expressing subclusters and two lacking COL22A1 but with a clear fibre type profile expressing MYH7 or MYH1/2. Our findings reveal distinct myonuclei profiles of the human MTJ, a weak link in the musculoskeletal system, which is selectively affected in pathological conditions, from muscle strains to muscular dystrophies.

molecular biology↗