Bridging the muscle genome to phenome across multiple biological scales
Author:
Sundar SaiLavanyaa12ORCID,
Rimkus Barbora12,
Meemaduma Prabath S.32,
deLap Samuel12,
LaFave Nicholas12,
Racca Alice W.12,
Hettige Pabodha32,
Moore Jeffrey12,
Gage Matthew32,
Shehaj Andrea12,
Konow Nicolai12ORCID
Affiliation:
1. Department of Biological Sciences, University of Massachusetts, Lowell, UK
2. UMass Movement Center, University of Massachusetts, Lowell, UK
3. Department of Chemistry. University of Massachusetts, Lowell, UK
Abstract
Muscle is highly hierarchically organized, with functions shaped by genetically controlled expression of protein ensembles with different isoform profiles at the sarcomere scale. However, it remains unclear how isoform profiles shape whole muscle performance. We compared two mouse hind limb muscles, the slow, relatively parallel-fibered soleus (SOL) and the faster, more pennate-fibered tibialis anterior (TA), across scales: from gene regulation, isoform expression and translation speed, to force-length-velocity-power for intact muscles. Expression of myosin heavy-chain (MHC) isoforms directly corresponded with contraction velocity. The fast-twitch TA with fast MHC isoforms had faster unloaded velocities (actin sliding velocity, VACTIN; peak fiber velocity, VMAX) than slow-twitch SOL. For SOL, VACTIN was biased towards VACTIN for purely slow MHC I, despite this muscle's even fast and slow MHC isoform composition. Our multi-scale results clearly identified a consistent and significant dampening in fiber shortening velocities for both muscles, underscoring an indirect correlation between VACTIN and fiber VMAX that may be influenced by differences in fiber architecture, along with internal loading due to both passive and active effects. These influences correlate with the increased peak force and power in the slightly more pennate TA, leading to a broader length range of near-optimal force production. Conversely, a greater force-velocity curvature in the near-parallel fibered SOL highlights the fine-tuning by molecular-scale influences including myosin heavy and light chain expression along with whole muscle characteristics. Our results demonstrate that the individual gene, protein, and whole fiber characteristics do not directly reflect overall muscle performance but that intricate fine-tuning across scales shapes specialized muscle function.
Funder
National Institutes of Health
American Heart Association
University of Massachusetts Lowell
Publisher
The Company of Biologists
Subject
Insect Science,Molecular Biology,Animal Science and Zoology,Aquatic Science,Physiology,Ecology, Evolution, Behavior and Systematics