Allison M. Owen

Disuse is often suggested as a major driver of quadriceps pathology following anterior cruciate ligament reconstruction (ACLR). This study identifies shared and unique gene signatures that occur early with ACLR and unilateral lower limb suspension (ULLS), highlighting ACLR-specific responses that likely contribute to prolonged quadriceps atrophy and weakness.

Satellite cell abundance and function are negatively affected by chronic kidney disease (CKD). Using primary myogenic progenitor cells (MPCs) cultured from patients with late-stage CKD and matched controls, we expose cells to CKD or control serum and identify metallothionein-induced zinc deficiency as both a cell-autonomous and nonautonomous consequence of CKD on MPCs. We find zinc deficiency likely attenuates myogenesis through an AKT-FOXO1 signaling cascade, which can be partially rescued by supplementation of exogenous zinc.

Muscle stem cells, or satellite cells (SCs), decline in number throughout the lifespan and may become senescent in very old age. Whether and how remaining SCs contribute to muscle adaptation in the oldest-old is unclear. Using acute mechanical overload in geriatric SC replete and depleted mice (28-month-old) combined with single-cell RNA-sequencing, we show: (i) subsets of geriatric SCs display signs of senescence as well as normal fate progression during overload, (ii) SCs express markers that may contribute to the regulation of innervation, (iii) the presence of SCs during overload enhances global intercellular communication and increases mRNA levels of the cell surface receptor Cd74 in immune cells, (iv) macrophage migration inhibitory factor (Mif), the primary ligand for CD74, is enriched in fibrogenic cells and is more pronounced in the absence of SCs—perhaps to normalize dysregulated fibrotic signaling and migration in macrophages, and (v) SCs influence cell fate dynamics to promote the canonical macrophage response to hypertrophic loading. Our findings expose the behavior of SCs in response to mechanical loading in the oldest-old in vivo and reveal a SC–macrophage–fibrogenic cell circuit in geriatric muscle that could support an early proadaptive inflammatory environment.

Knee osteoarthritis contributes substantially to worldwide disability. Post‐traumatic osteoarthritis (PTOA) develops secondary to joint injury, such as ligament rupture, and there is increasing evidence suggesting a key role for inflammation in the aetiology of PTOA and associated functional deficits. Colony stimulating factor 1 receptor (CSF1‐R) has been implicated in the pathogenesis of musculoskeletal degeneration following anterior cruciate ligament (ACL) injury. We sought to assess the efficacy of CSF1‐R inhibition to mitigate muscle and joint pathology in a mouse model of PTOA. Four‐month‐old mice were randomized to receive a CSF1‐R inhibitor and studied for 7 or 28 days after joint injury. Additionally, we profiled synovial fluid samples for CSF1‐R from patients with injury to their ACL. Transcriptomic analysis of quadriceps muscle and articular cartilage in CSF1‐R inhibitor‐treated animals at 7 days after injury revealed elevated chondrocyte differentiation within articular cartilage and enhanced metabolic and contractile gene expression within skeletal muscle. At 28 days post‐injury, CSF1‐R inhibition attenuated PTOA severity and mitigated skeletal muscle atrophy. Patient synovial fluid CSF1‐R levels correlated with matrix metalloproteinase 13, a prognostic marker and molecular effector of PTOA. Our findings support an opportunity for CSF1‐R targeting to mitigate the severity of PTOA and muscle atrophy after joint injury. image Key points: Posttraumatic osteoarthritis (PTOA) of the knee commonly results from direct injury to the joint, which is characterized by pain, weakness, and disability. Induction of colony stimulating factor one receptor (CSF1‐R) is positively associated with knee trauma severity, and the initial acute inflammatory state suppresses muscle recovery and degrades articular cartilage. Skeletal muscle and articular cartilage transcriptomic response following direct joint injury in a murine model of PTOA is rescued by pharmacological inhibition of CSF1‐R. CSF1‐R inhibition mitigated skeletal muscle atrophy and attenuated PTOA severity and synovitis. Patient synovial fluid CSF1‐R levels correlated with matrix metalloproteinase 13, a prognostic marker and molecular effector of PTOA, offering further evidence for CSF1‐R as a therapeutic target across musculoskeletal tissues after injury.

There remains a critical need to define molecular pathways underlying sarcopenia to identify putative therapeutic targets. Research in the mechanisms of aging and sarcopenia relies heavily on preclinical rodent models. In this issue of the JCI , Kerr et al. implemented a clinically-relevant sarcopenia classification system of aged C57BL/6J mice, capturing sarcopenia prevalence across both sexes. The authors performed detailed physiological, molecular, and energetic analyses and demonstrated that mitochondrial biogenesis, oxidative capacity, and AMPK-autophagy signaling decreased as sarcopenia progressed in male mice. Sarcopenia was less prevalent in female mice with fewer alterations compared with the male-affected processes. The findings highlight factors beyond age as necessary for classifying the sarcopenic phenotype in rodent models, reveal sexual dimorphism across the trajectory of age-related declines in muscle mass and function in a commonly used rodent model, and provide insight into sex-dependent molecular alterations associated with sarcopenia progression.

Cell-free hemoglobin (CFH) is elevated in the airspace of most patients with acute respiratory distress syndrome and causes severe inflammation. Here, we identify that CFH contributes to macrophage-induced cytokine production via Toll-like receptor 4 (TLR4) and myeloid differentiation primary response 88 (MyD88) signaling. These data increase our knowledge of the mechanisms through which CFH contributes to lung injury and may inform development of targeted therapeutics to attenuate inflammation.

Musculoskeletal disorders contribute substantially to worldwide disability. Anterior cruciate ligament (ACL) tears result in unresolved muscle weakness and posttraumatic osteoarthritis (PTOA). Growth differentiation factor 8 (GDF8) has been implicated in the pathogenesis of musculoskeletal degeneration following ACL injury. We investigated GDF8 levels in ACL-injured human skeletal muscle and serum and tested a humanized monoclonal GDF8 antibody against a placebo in a mouse model of PTOA (surgically induced ACL tear). In patients, muscle GDF8 was predictive of atrophy, weakness, and periarticular bone loss 6 months following surgical ACL reconstruction. In mice, GDF8 antibody administration substantially mitigated muscle atrophy, weakness, and fibrosis. GDF8 antibody treatment rescued the skeletal muscle and articular cartilage transcriptomic response to ACL injury and attenuated PTOA severity and deficits in periarticular bone microarchitecture. Furthermore, GDF8 genetic deletion neutralized musculoskeletal deficits in response to ACL injury. Our findings support an opportunity for rapid targeting of GDF8 to enhance functional musculoskeletal recovery and mitigate the severity of PTOA after injury.

Pretreatment with 3-deacyl 6-acyl phosphorylated hexaacyl disaccharide; a novel synthetic Toll-like receptor 4 agonist, preserves kidney function during ischemia-reperfusion injury-induced acute kidney injury.

Immunocompromised populations are highly vulnerable to developing life-threatening infections. Strategies to protect patients with weak immune responses are urgently needed. Employing trained immunity, whereby innate leukocytes undergo reprogramming upon exposure to a microbial product and respond more robustly to subsequent infection, is a promising approach. Previously, we demonstrated that the TLR4 agonist monophosphoryl lipid A (MPLA) induces trained immunity and confers broad resistance to infection. TLR4 signals through both MyD88- and TRIF-dependent cascades, but the relative contribution of each pathway to induction of trained immunity is unknown. Here, we show that MPLA-induced resistance to Staphylococcus aureus infection is lost in MyD88-KO, but not TRIF-KO, mice. The MyD88-activating agonist CpG (TLR9 agonist), but not TRIF-activating Poly I:C (TLR3 agonist), protects against infection in a macrophage-dependent manner. MPLA- and CpG-induced augmentation of macrophage metabolism and antimicrobial functions is blunted in MyD88-, but not TRIF-KO, macrophages. Augmentation of antimicrobial functions occurs in parallel to metabolic reprogramming and is dependent, in part, on mTOR activation. Splenic macrophages from CpG-treated mice confirmed that TLR/MyD88-induced reprogramming occurs in vivo. TLR/MyD88-triggered metabolic and functional reprogramming was reproduced in human monocyte-derived macrophages. These data show that MyD88-dependent signaling is critical in TLR-mediated trained immunity.