## 2 Materials and Methods
### Muscle Analyses  
Immunofluorescent staining was performed using the protocol of [PERSON] et al. [20]. Frozen muscle biopsies were cut into 5-um thick cryosections using a cryostat at \(-20\)\({}^{\circ}\)C and thaw mounted on uncoated pre-cleaned glass slides. Samples were stained with antibodies against CD31 (1:50, endothelial cell mouse IGG1 Dako M0823), myosin heavy chain I (clone A4.840 (slow isoform), 1:25; DSHB, Iowa City, IA, USA), and laminin (1:1000, Abcam ab11575, Abcam, Cambridge, MA, USA). For immunofluorescence detection, the secondary antibodies used were as follows: myosin heavy chain type I (cloneA4.840) (goat anti-mouse Alexa Fluor 488, 1:500, Invitrogen, Waltham, MA, USA); laminin (goat anti-rabbit Alexa Fluor 647, 1:500, Invitrogen); and CD31 (goat anti-rabbit Alexa Fluor 555, 1:500, Invitrogen, Molecular Probes, Carlsbad, CA, USA). Nuclei were labelled with DAPI (4\({}^{\prime}\),6-diamidino-2-phenylindole) (1:20,000, Sigma-Aldrich, Oakville, ON, Canada) prior to cover slipping slides with fluorescent mounting media (DAKO, Burlington, ON, Canada). Slides were viewed and automatically captured using 10\(\times\) objective on a modified Olympus BX51 fluorescence microscope with a customized spinning disk unit (DSU, Olympus), computer-controlled excitation and emission filter wheels (Olympus), 3-axis high-accuracy computer-controlled stepping motor specimen stage (Grid Encoded Stage, Ludl Electronic Products, Hawthorne, NY, USA), ultra-high sensitivity monochrome electron multiplier CCD camera (C9100-02, Hamamatsu Photonics, Hamamatsu City, Japan), and controlling software (StereoInvestigator; MBF BioScience, Williston, VT, USA). Quantitative images were analyzed using image] version 1.52a, National Institutes of Health, USA. All image recordings and analyses were performed by an investigator blinded to subject coding. Type I and type II muscle fiber distribution, size, central nuclei, myonuclear content, and domain size were analyzed using a mean of 319 \(\pm\) 136 and 280 \(\pm\) 135 fibers for pre-and post-analyses, respectively. For cross-sectional area (CSA) measurements, each myofiber was traced along its laminin-stained border. Fiber circularity was calculated as perimeter\({}^{2}\)/4\(\pi\)CSA [21]. The mean circularity was 0.66 \(\pm\) 0.03 and 0.65 \(\pm\) 0.04 for pre- and post-measurements. No differences in fiber circularity were observed over time. Quantification of capillary content per fiber type was based on the work of [PERSON] et al. [22]. Quantification comprised (i) capillary contacts (CC), (ii) the capillary-to-fiber ratio (C/Fi), (iii) capillary-to-fiber perimeter exchange (CFPE) index, and (iv) capillary density (CD). A mean of 63 \(\pm\) 14 and 57 \(\pm\) 15 muscle fibers were analyzed for pre- and post-measurements. To analyze the ultrastructural characteristics of the skeletal muscle fibers, a muscle biopsy sample from each of the first 11 consecutive patients was dissected in 1-mm blocks and immediately fixed by immersion in a solution of 2% glutaraldehyde in 0.05 M sodium cacodylate buffer (pH 7.3) at 4\({}^{\circ}\)C. Following fixation, samples were post-fixed with 2% osmium tetroxide in 0.05 M sodium cacodylate buffer (pH 7.3) for 1 h at room temperature and subsequently dehydrated through ascending concentrations of acetone. Dehydrated samples were impregnated overnight in a 1:1 mixture of acetone and analdite epoxy resin at room temperature, followed by impregnation in 100% Araldite epoxy resin at 40 \({}^{\circ}\)C for 3 h, and finally embedded in Araldite epoxy resin at 60 \({}^{\circ}\)C for 24 h. Semithin sections (0.5 \(\upmu\)m) were cut on a Leica EM UC6 microtome and stained with a solution of thionin and methylene blue (0.1% aqueous solution) for light microscopic examination, to identify skeletal muscle fibers. Representative pictures of longitudinally and transversally cut my of fibers were scanned with an Axioscan Z1 (Carl Zeiss Microscopy GmbH, Jena, Germany) and analyzed with Zen 3.3 (Blue edition) software (Carl Zeiss Microscopy GmbH, Jena, Germany).