Oral Presentation 30th Australian and New Zealand Bone and Mineral Society Annual Scientific Meeting 2020

Bone geometry is altered by follistatin-induced muscle growth in adult male mice (#3)

Audrey S Chan 1 , Narelle E McGregor 2 , Ingrid J Poulton 2 , Justin P Hardee 1 , Ellie HJ Cho 3 , T. John Martin 2 , Paul Gregorevic 1 , Natalie A Sims 2 , Gordon S Lynch 1
  1. Centre for Muscle Research, Dept Anatomy and Physiology, The University of Melbourne, Parkville, VIC, Australia
  2. Bone Cell Biology and Disease, St Vincent's Institute of Medical Research, Fitzroy, VIC, Australia
  3. Biological Optical Microscopy Platform, The University of Melbourne, Melbourne, VIC, Australia

Skeletal muscle size and the forces generated during muscle contraction shape bone structure during growth by providing mechanical stress to the developing skeleton. This is particularly evident in myostatin-null mice, where larger muscles increase bone mass and alter bone shape during development. However, whether muscle hypertrophy can influence the shape and strength of adult bones is unknown.

To answer this question, we assessed bone structure after inducing hypertrophy in the lower hindlimb muscles of 14-week-old adult male mice by intramuscular injections of recombinant adeno-associated virus vectors expressing follistatin (Fst), a potent antagonist of myostatin. To separate the local influence of Fst-induced muscle growth from any systemic action of Fst we used two Fst isoforms: the tissue-bound 288 amino acid isoform (Fst-288), and the longer circulating isoform (Fst-315).

Both Fst isoforms increased the mass of individual muscles, including the tibialis anterior (by 45%), extensor digitorum longus (by 45%), plantaris (by 46%), soleus (by 69%) and gastrocnemius (by 53%). In both Fst-treated cohorts, the anterior crest of the tibia, adjacent to the tibialis anterior muscle, was lengthened. Additionally, cortical bone adjacent to the hypertrophic muscles receded inward toward the central axis; an event driven by bone resorption on the periosteal surface abutting the gastrocnemius, and abundant osteoblast formation on the adjacent endocortical surface. In addition, expression of the circulating Fst isoform (Fst-315), but not tissue-bound Fst-288, increased trabecular bone volume. This was observed to a similar extent in both the tibia (increased by 53%) and the distal femur (increased by 40%), even though the latter is not adjacent to hypertrophied muscle.

These findings indicate that circulating Fst can increase trabecular bone volume, and that Fst-induced muscle hypertrophy in adult mice modifies bone shape. We conclude that muscle growth is capable of conferring local changes in bone shape, even in the adult skeleton.