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1.
Scand J Med Sci Sports ; 30(11): 2101-2115, 2020 Nov.
Article in English | MEDLINE | ID: mdl-32762021

ABSTRACT

High-load eccentric training reputedly produces greater muscle hypertrophy than concentric training, possibly due to greater loading and/or inflammation. We quantified the temporal impact of combined maximal concentric-eccentric training vs maximal concentric training on muscle cross-sectional area (CSA), volume, and targeted mRNA expression (93 transcripts). Eight recreationally active males (24 ± 5 years, BMI 23.5 ± 2.5 kg/m2 ) performed 3 x 30 maximal eccentric isokinetic knee extensions and 2 x 30 maximal concentric knee extensions in dominant limb (ECC + CON) and 5 x 30 maximal concentric contractions (CON) in the non-dominant limb for 12 weeks (all 90°/s, 3x/wk). Quadriceps muscle CSA and volume were measured at baseline, 28 days (d), and 84 d in both limbs (3T MRI). Resting vastus lateralis biopsies were obtained from both limbs at baseline, 24 hours (h), 7, 28, and 84 d for mRNA abundance measurements (RT-PCR microfluidic cards). Work output was greater throughout training in ECC + CON vs CON (20.8 ± 9.7%, P < .001). Muscle CSA increased from baseline in both limbs at 28 d (CON 4.3 ± 2.6%, ECC + CON 4.0 ± 1.9%, both P < .001) and 84d (CON 3.9 ± 2.3%, ECC + CON 4.0 ± 3.1%, both P < .001), and muscle volume and isometric strength at 84 d (CON 44.8 ± 40.0%, P < .001; ECC + CON 36.9 ± 40.0%, P < .01), but no between-limb differences existed in any parameter. Ingenuity Pathway Analysis identified several cellular functions associated with regulation of muscle mass and metabolism as altered by both modalities at 24 h and 7 d, but particularly with ECC + CON. However, mRNA responses waned thereafter, regardless of modality. Initial muscle mRNA responses to training did not reflect chronic training-induced hypertrophy. Moreover, ECC + CON did not produce greater hypertrophy than CON, despite greater loading throughout and a differential mRNA response during the initial training week.


Subject(s)
Muscle Strength , Quadriceps Muscle/anatomy & histology , Quadriceps Muscle/metabolism , Resistance Training/methods , Transcription, Genetic , Adult , Body Mass Index , Humans , Inflammation/physiopathology , Isometric Contraction , Leg/physiology , Male , Quadriceps Muscle/physiopathology , Time Factors , Young Adult
2.
Sci Transl Med ; 12(541)2020 04 29.
Article in English | MEDLINE | ID: mdl-32350131

ABSTRACT

Myotonic dystrophy type 1 (DM1) is an RNA-based disease with no current treatment. It is caused by a transcribed CTG repeat expansion within the 3' untranslated region of the dystrophia myotonica protein kinase (DMPK) gene. Mutant repeat expansion transcripts remain in the nuclei of patients' cells, forming distinct microscopically detectable foci that contribute substantially to the pathophysiology of the condition. Here, we report small-molecule inhibitors that remove nuclear foci and have beneficial effects in the HSALR mouse model, reducing transgene expression, leading to improvements in myotonia, splicing, and centralized nuclei. Using chemoproteomics in combination with cell-based assays, we identify cyclin-dependent kinase 12 (CDK12) as a druggable target for this condition. CDK12 is a protein elevated in DM1 cell lines and patient muscle biopsies, and our results showed that its inhibition led to reduced expression of repeat expansion RNA. Some of the inhibitors identified in this study are currently the subject of clinical trials for other indications and provide valuable starting points for a drug development program in DM1.


Subject(s)
Myotonic Dystrophy , Animals , Cyclin-Dependent Kinases , Disease Models, Animal , Humans , Mice , Myotonic Dystrophy/drug therapy , Myotonic Dystrophy/genetics , RNA , RNA Splicing/genetics , Trinucleotide Repeat Expansion/genetics
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