Molecular signatures of age-associated chronic degeneration of shoulder muscles

Abstract

Chronic muscle diseases are highly prevalent in the elderly causing severe mobility limitations, pain and frailty. The intrinsic molecular mechanisms are poorly understood due to multifactorial causes, slow progression with age and variations between individuals. Understanding the underlying molecular mechanisms could lead to new treatment options which are currently limited. Shoulder complaints are highly common in the elderly, and therefore, muscles of the shoulder's rotator cuff could be considered as a model for chronic age-associated muscle degeneration. Diseased shoulder muscles were characterized by muscle atrophy and fatty infiltration compared with unaffected shoulder muscles. We confirmed fatty infiltration using histochemical analysis. Additionally, fibrosis and loss of contractile myosin expression were found in diseased muscles. Most cellular features, including proliferation rate, apoptosis and cell senescence, remained unchanged and genome-wide molecular signatures were predominantly similar between diseased and intact muscles. However, we found down-regulation of a small subset of muscle function genes, and up-regulation of extracellular region genes. Myogenesis was defected in muscle cell culture from diseased muscles but was restored by elevating MyoD levels. We suggest that impaired muscle functionality in a specific environment of thickened extra-cellular matrix is crucial for the development of chronic age-associated muscle degeneration.

Endothelin-1 induces cellular senescence and fibrosis in cultured myoblasts. A potential mechanism of aging-related sarcopenia

“…For this reason, we decided to study its effects on cultured muscle cells using a well-described experimental cellular model; mouse myoblast C 2 C 12 cells [ 30 ]. We analyzed the effect of ET-1 on some of the best studied aging-related aspects of myoblast biology, in particular on cellular senescence and ECM protein synthesis, since aging is associated with reductions in both muscle stem cell function and muscle regeneration potential, and with increased muscular fibrosis [ 4 , 31 ].…”

“…Senescence induced by ET-1 at vascular level has been involved in some pathologies [ 37 ], such as diabetes [ 38 ], varicosity [ 39 ] and thrombosis [ 40 ]. So, senescence induced by ET-1 at muscle level could be implicated in the development of fibrosis, exacerbating muscle damage, as the regenerative potential of skeletal muscle declines with age and this impairment is associated with an increase in tissue fibrosis [ 4 , 31 ]. Brack et al showed that muscle stem cells (satellite cells) from aged mice tend to convert from a myogenic to a fibrogenic lineage as they begin to proliferate and increase tissue fibrosis [ 4 ].…”

“…According to this data, the fibrosis we found in the gastrocnemius and tibialis anterior muscles from old mice could explain at least in part the reduction in muscle force. Raz et al suggested that chronic age-associated muscle degeneration was associated with higher fibrosis in muscle [ 31 ] and the relationship between muscular fibrosis and loss of strength has also been described in several muscular dystrophies [ 57 ]. With respect to senescence increased in old mice, previous results from our group [ 19 , 45 ] are in agreement, as they found that old mice had high levels of serum phosphate linked to increased expression of ILK and senescence genes.…”

Gene Expression Patterns Analysis in the Supraspinatus Muscle after a Rotator Cuff Tear in a Mouse Model

“…Identification of gene expression patterns of rotator cuff muscle cells after a rotator cuff tear would be the first step and an important determinant in understanding the rotator cuff tear-related muscle changes and improving outcomes of rotator cuff repair surgery. Several studies have suggested various causes and mechanisms for muscle changes, such as atrophy and degeneration [9, 10, 21–25]; however, despite this, much remains unknown. Progression of muscle degeneration, atrophy, and fatty infiltration is usually caused by abnormal signaling processes in muscle cells [25].…”

“…Several studies have suggested various causes and mechanisms for muscle changes, such as atrophy and degeneration [9, 10, 21–25]; however, despite this, much remains unknown. Progression of muscle degeneration, atrophy, and fatty infiltration is usually caused by abnormal signaling processes in muscle cells [25]. Abnormal muscle cell activities are the results of external stimuli, such as physical damage or aging, which lead to differentiation into fat cells or fibrous tissue and ultimately myocyte destruction (instead of normal myocyte differentiation) [26].…”