Beyond Myosin Heavy Chains in Human Skeletal Muscle Heterogeneity

ABSTRACT: Skeletal muscle is an inherently heterogenous tissue comprised primarily of myofibers, which are historically classified into three distinct fiber types in humans: one “slow” (type 1) and two “fast” (type 2A and type 2X), delineated by the expression of myosin heavy chain isoforms (MYHs). However, whether discrete fiber types exist or whether fiber heterogeneity reflects a continuum remains unclear. Furthermore, whether MYHs are the main classifiers of skeletal muscle fibers has not been examined in an unbiased manner. Through the development and application of novel transcriptomic and proteomic workflows, applied to 1050 and 1038 single muscle fibers from human vastus lateralis, respectively, we show that MYHs are not the principal drivers of skeletal muscle fiber heterogeneity. Instead, ribosomal heterogeneity drives the majority of variance between skeletal muscle fibers in a continual fashion, independent of slow/fast fiber type. Furthermore, whilst slow and fast fiber clusters can be identified, described by their contractile and metabolic profiles, our data challenge the concept that type 2X are phenotypically distinct from other fast fibers at an omics level. Moreover, MYH-based classifications do not adequately describe the phenotype of skeletal muscle fibers in one of the most common genetic muscle diseases, nemaline myopathy. Our data question the currently accepted model of multiple distinct fiber types based on the expression of MYHs in humans and identifies ribosomal heterogeneity as a major driver of skeletal muscle fiber heterogeneity, opening a new field of research within skeletal muscle physiology.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skeletal Muscle Fiber

DISEASE(S): Nemaline Myopathy

SUBMITTER: Roger Moreno Justicia  

LAB HEAD: Atul Shahaji

PROVIDER: PXD046863 | Pride | 2025-02-27

REPOSITORIES: Pride