The Role of Slow-Twitch Skeletal Muscle in the Musculoskeletal Endocrine Axis
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In addition to coupling mechanically to produce movement, the musculoskeletal unit has an endocrine function, capable of signaling to distant tissues as well as locally through the release of hormone-like molecules. Musculoskeletal disuse triggers loss of bone and skeletal muscle function while exercise improves musculoskeletal health and protects against chronic disease. We investigated potential crosstalk pathways within the musculoskeletal unit involving, (1) muscle derived BAIBA in muscle-to-bone crosstalk and (2) bone MBTPS1 in bone-to-muscle crosstalk. To assess the impact of BAIBA on muscle and bone properties, mice were immobilized for two weeks via hind limb suspension while receiving L-BAIBA. Fast twitch extensor digitorum longus (EDL) muscles and slow twitch soleus muscles were then isolated for ex vivo contractility testing and tibia was obtained for analysis of trabecular bone content. In muscle, L-BAIBA supplementation showed no effect on muscle mass or EDL contractile function but increased slow-twitch soleus contractile force by 15% over non-supplemented mice. In addition, the rate of soleus muscle contractile force development was greater in the supplemented group compared to control. In bone, L-BAIBA receiving mice had higher tibia BV/TV compared to control. Next, we investigated the role of Mbtps1 in bone-to-muscle crosstalk using osteocyte-specific Mbtps1 conditional knock-out mouse (cKO) using Dmp1-driven Cre. MBTPS1 is a widely expressed proprotein convertase involved in proprotein processing within the secretory pathway. In bone, MBTPS1 is required for normal skeletal development and mineralization. Ex vivo contractility of cKO EDL and soleus muscles revealed an age-related enhancement of slow-twitch soleus muscle contractile force, muscle size and regeneration of slow type-1 muscle fibers compared to control littermates while EDL muscle properties remained largely unaffected. Subsequent gene array analysis uncovered upregulation of genes related to muscle contraction, oxidative metabolism and muscle regeneration in the cKO soleus. These findings reveal possible targeted impacts of musculoskeletal auto-, para-, and endocrine signaling among slow twitch skeletal muscle and support the novel paradigm of relevant musculoskeletal crosstalk axes in the maintenance of muscle and bone health.
Table of Contents
Introduction -- Methodology -- Results -- Discussion