No abstract

The coordinated movement of many organisms relies on efficient nerve–muscle communication at the neuromuscular junction (NMJ), a peripheral synapse composed of a presynaptic motor axon terminal, a postsynaptic muscle specialization, and non‐myelinating terminal Schwann cells. NMJ dysfunctions are caused by traumatic spinal cord or peripheral nerve injuries as well as by severe motor pathologies. Compared to the central nervous system, the peripheral nervous system displays remarkable regenerating abilities; however, this capacity is limited by the denervation time frame and depends on the establishment of permissive regenerative niches. At the injury site, detailed information is available regarding the cells, molecules, and mechanisms involved in nerve regeneration and repair. However, a regenerative niche at the final functional step of peripheral motor innervation, i.e. at the mature neuromuscular synapse, has not been deciphered. In this review, we integrate classic and recent evidence describing the cells and molecules that could orchestrate a dynamic ecosystem to accomplish successful NMJ regeneration. We propose that such a regenerative niche must ensure at least two fundamental steps for successful NMJ regeneration: the proper arrival of incoming regenerating axons to denervated postsynaptic muscle domains, and the resilience of those postsynaptic domains, in morphological and functional terms. We here describe and combine the main cellular and molecular responses involved in each of these steps as potential targets to help successful NMJ regeneration.

Obesity is a major public health concern and is associated with decreased muscle quality (i.e., strength, metabolism). Muscle from obese adults is characterized by increases in fatty, fibrotic tissue that decreases the force producing capacity of muscle and impairs glucose disposal. Fibro/adipogenic progenitors (FAPs) are muscle resident, multipotent stromal cells that are responsible for muscle fibro/fatty tissue accumulation. Additionally, they are indirectly involved in muscle adaptation through their promotion of myogenic (muscle-forming) satellite cell proliferation and differentiation. In conditions similar to obesity that are characterized by chronic muscle degeneration, FAP dysfunction has been shown to be responsible for increased fibro/fatty tissue accumulation in skeletal muscle, and impaired satellite cell function. The role of metabolic stress in regulating FAP differentiation and paracrine function in skeletal muscle is just beginning to be unraveled. Thus, the present review aims to summarize the recent literature on the role of metabolic stress in regulating FAP differentiation and paracrine function in skeletal muscle, and the mechanisms responsible for these effects. Furthermore, we will review the role of physical activity in reversing or ameliorating the detrimental effects of obesity on FAP function.

Cellular senescence is the irreversible arrest of normally dividing cells and is driven by the cell cycle inhibitors Cdkn2a, Cdkn1a, and Trp53. Senescent cells are implicated in chronic diseases and tissue repair through their increased secretion of pro‐inflammatory factors known as the senescence‐associated secretory phenotype (SASP). Here, we use spatial transcriptomics and single‐cell RNA sequencing (scRNAseq) to demonstrate that cells displaying senescent characteristics are “transiently” present within regenerating skeletal muscle and within the muscles of D2‐mdx mice, a model of Muscular Dystrophy. Following injury, multiple cell types including macrophages and fibrog–adipogenic progenitors (FAPs) upregulate senescent features such as senescence pathway genes, SASP factors, and senescence‐associated beta‐gal (SA‐β‐gal) activity. Importantly, when these cells were removed with ABT‐263, a senolytic compound, satellite cells are reduced, and muscle fibers were impaired in growth and myonuclear accretion. These results highlight that an “acute” senescent phenotype facilitates regeneration similar to skin and neonatal myocardium.

The aim of this study was to examine the activation of skeletal muscle signaling pathways related to protein synthesis and the gene expression of regeneration/degradation markers following repeated bouts of eccentric cycling. Nine untrained men (25.4 ± 1.9 yr) performed two 30-min eccentric cycling bouts (ECC1, ECC2) at 85% of maximal concentric workload, separated by 2 wk. Muscle biopsies were taken from the vastus lateralis before and 2 h after each bout. Indirect markers of muscle damage were assessed before and 24–48 h after exercise. Changes in the Akt/mammalian target of rapamycin (mTOR)/rbosomal protein S6 kinase 1 (S6K1)/ribosomal protein S6 (rpS6) and MAPK signaling pathways were measured by Western blot and changes in mRNA expression of IL-6 and IL-1β, and myogenic regulatory factors (MRFs) were measured by real-time PCR. ECC1 induced greater increases in indirect markers of muscle damage compared with ECC2. Phosphorylation of S6K1 and rpS6 increased after both exercise bouts ( P < 0.05), whereas phosphorylation of mTOR increased after ECC2 only ( P = 0.03). Atrogin-1 mRNA expression decreased after ECC1 and ECC2 ( P < 0.05) without changes in muscle RING-finger protein-1 mRNA. Basal mRNA levels of myoblast determination protein-1 (MyoD), MRF4, and myogenin were higher 2 wk after ECC1 ( P < 0.05). MRF4 mRNA increased after ECC1 and ECC2 ( P < 0.05), whereas MyoD mRNA expression increased only after ECC1 ( P = 0.03). Phosphorylation of JNK and p38 MAPK increased after both exercise bouts ( P < 0.05), similar to IL-6 and IL-1β mRNA expression. All together, these results suggest that differential regulation of the mTOR pathway and MRF expression could mediate the repeated bout effect observed between an initial and secondary bout of eccentric exercise.