Muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin-1 were identified more than 10 years ago as two muscle-specific E3 ubiquitin ligases that are increased transcriptionally in skeletal muscle under atrophy-inducing conditions, making them excellent markers of muscle atrophy. In the past 10 years much has been published about MuRF1 and MAFbx with respect to their mRNA expression patterns under atrophy-inducing conditions, their transcriptional regulation, and their putative substrates. However, much remains to be learned about the physiological role of both genes in the regulation of mass and other cellular functions in striated muscle. Although both MuRF1 and MAFbx are enriched in skeletal, cardiac, and smooth muscle, this review will focus on the current understanding of MuRF1 and MAFbx in skeletal muscle, highlighting the critical questions that remain to be answered.

Skeletal muscle atrophy and the E3 ubiquitin ligases MuRF1 and MAFbx/atrogin-1

Are designed landscapes conceived as geometric compositions or abstractions of nature incompatible with sustainable design? Does mimesis result in the only truly sustainable form in the landscape? This paper attempts to answer these questions by drawing on the observations of practitioners and educators in the field as well as investigating a range of built work for sustainable qualities. The built work is categorized according to four approaches to form genesis, geometric composition, abstractions of nature, mimesis, and combinations of the three. It is suggested here that there is no single formal strategy that must be used in order to achieve sustainability.

Summary comments

Immune-mediated tissue regeneration driven by a biomaterial scaffold is emerging as an innovative regenerative strategy to repair damaged tissues. We investigated how biomaterial scaffolds shape the immune microenvironment in traumatic muscle wounds to improve tissue regeneration. The scaffolds induced a pro-regenerative response, characterized by an mTOR/Rictor-dependent T helper 2 pathway that guides interleukin-4–dependent macrophage polarization, which is critical for functional muscle recovery. Manipulating the adaptive immune system using biomaterials engineering may support the development of therapies that promote both systemic and local pro-regenerative immune responses, ultimately stimulating tissue repair.

https://science.sciencemag.org/content/sci/352/6283/366.full.pdf

Developing a pro-regenerative biomaterial scaffold microenvironment requires T helper 2 cells.

Tissue development is orchestrated by the coordinated activities of both chemical and physical regulators. While much attention has been given to the role that chemical regulators play in driving development, researchers have recently begun to elucidate the important role that the mechanical properties of the extracellular environment play. For instance, the stiffness of the extracellular environment has a role in orienting cell division, maintaining tissue boundaries, directing cell migration, and driving differentiation. In addition, extracellular matrix stiffness is important for maintaining normal tissue homeostasis, and when matrix mechanics become imbalanced, disease progression may ensue. In this article, we will review the important role that matrix stiffness plays in dictating cell behavior during development, tissue homeostasis, and disease progression.

https://www.tandfonline.com/doi/pdf/10.1080/15476278.2015.1019687

Tissue Stiffness Dictates Development, Homeostasis, and Disease Progression

https://www.cell.com/trends/biochemical-sciences/pdf/S0968-0004(14)00027-9.pdf

FOXO transcription factors: key regulators of cellular quality control

Sarcopenia is one of the leading causes of disability in the elderly. Despite the growing prevalence of sarcopenia, the molecular mechanisms that control aging-related changes in muscle mass are not fully understood. The ubiquitin proteasome system is one of the major pathways that regulate muscle protein degradation, and this system plays a central role in controlling muscle size. Atrogin-1 and MuRF-1 are two E3 ubiquitin ligases that are important regulators of ubiquitin-mediated protein degradation in skeletal muscle. In this review, we will discuss: (i) aging-related changes to skeletal muscle structure and function; (ii) the regulation of protein synthesis and protein degradation by IGF-1, TGF-β, and myostatin, with emphasis on the control of atrogin-1 and MuRF-1 expression; and (iii) the potential for modulating atrogin-1 and MuRF-1 expression to treat or prevent sarcopenia.

/pdf/atrogin-1-murf-1-and-sarcopenia-3rt5izy406.pdf

Atrogin-1, MuRF-1, and sarcopenia.

Advanced age is associated with increases in muscle passive stiffness, but the contributors to the changes remain unclear. Our purpose was to determine the relative contributions of muscle fibers and extracellular matrix (ECM) to muscle passive stiffness in both adult and old animals. Passive mechanical properties were determined for isolated individual muscle fibers and bundles of muscle fibers that included their associated ECM, obtained from tibialis anterior muscles of adult (8–12 mo old) and old (28–30 mo old) mice. Maximum tangent moduli of individual muscle fibers from adult and old muscles were not different at any sarcomere length tested. In contrast, the moduli of bundles of fibers from old mice was more than twofold greater than that of fiber bundles from adult muscles at sarcomere lengths >2.5 μm. Because ECM mechanical behavior is determined by the composition and arrangement of its molecular constituents, we also examined the effect of aging on ECM collagen characteristics. With aging, muscle ECM hydroxyproline content increased twofold and advanced glycation end-product protein adducts increased threefold, whereas collagen fibril orientation and total ECM area were not different between muscles from adult and old mice. Taken together, these findings indicate that the ECM of tibialis anterior muscles from old mice has a higher modulus than the ECM of adult muscles, likely driven by an accumulation of densely packed extensively crosslinked collagen.

/pdf/intrinsic-stiffness-of-extracellular-matrix-increases-with-2c1a4k6eez.pdf

Intrinsic stiffness of extracellular matrix increases with age in skeletal muscles of mice.

Introduction: Transforming growth factor-beta (TGF-b) is a well-known regulator of fibrosis and inflammation in many tissues. During embryonic development, TGF-b signal- ing induces expression of the transcription factor scleraxis, which promotes fibroblast proliferation and collagen synthesis in tendons. In skeletal muscle, TGF-b has been shown to induce atrophy and fibrosis, but the effect of TGF-b on muscle contrac- tility and the expression of scleraxis and atrogin-1, an important regulator of muscle atrophy, were not known. Methods: We treated muscles from mice with TGF-b and measured force pro- duction, scleraxis, procollagen Ia2, and atrogin-1 protein levels. Results: TGF-b decreased muscle fiber size and dramatically reduced maximum isometric force production. TGF-b also induced scleraxis expression in muscle fibroblasts, and increased procollagen Ia2 and atrogin-1 levels in muscles. Conclusion: These results provide new insight into the effect of TGF-b on muscle contractility and the molecular mechanisms behind TGF-b-mediated muscle atrophy and fibrosis. Muscle Nerve 45: 55-59, 2012

/pdf/transforming-growth-factor-beta-induces-skeletal-muscle-34ndq7czqi.pdf

Transforming growth factor-beta induces skeletal muscle atrophy and fibrosis through the induction of atrogin-1 and scleraxis.

https://deepblue.lib.umich.edu/bitstream/handle/2027.42/90076/21550_ftp.pdf;sequence=1

Physiological Loading of Tendons Induces Scleraxis Expression in Epitenon Fibroblasts

Numerous studies in muscle and tendon have identified a central role of the transforming growth factor-β (TGF-β) superfamily of cytokines in the regulation of extracellular matrix growth and remodeling, protein degradation, and cell proliferation and differentiation. We provide a novel framework for TGF-β and myostatin signaling in controlling the coordinated adaptation of both skeletal muscle and tendon tissue to resistance training.

/pdf/tgf-b-superfamily-signaling-in-muscle-and-tendon-adaptation-hcfkyomyip.pdf

Jonathan P. Gumucio

Papers

Atrogin-1, MuRF-1, and sarcopenia.

Intrinsic stiffness of extracellular matrix increases with age in skeletal muscles of mice.

Transforming growth factor-beta induces skeletal muscle atrophy and fibrosis through the induction of atrogin-1 and scleraxis.

Physiological Loading of Tendons Induces Scleraxis Expression in Epitenon Fibroblasts

TGF-β superfamily signaling in muscle and tendon adaptation to resistance exercise.