GM130 and p115 play a key role in the organisation of the early secretory pathway during skeletal muscle differentiation

Abstract

Skeletal muscle (SKM) differentiation is a highly regulated process leading to the formation of specialised cells with reorganised compartments and organelles, such as those of the early secretory pathway. During SKM differentiation the Golgi complex (GC) redistributes close to the nuclear envelope and in small distinct peripheral structures distributed throughout the myotube. Concurrently, GC elements closely associate with endoplasmic reticulum-exit sites (ERES). The mechanisms underlying this reorganisation and its relevance for SKM differentiation are poorly understood. Here, we show, by time-lapse imaging studies, that the changes in GC organisation involve GC fragmentation and redistribution of ERES with the formation of tightly associated GC-ERES units. We show that knockdown of GM130 (also known as GOLGA2) or p115 (also known as USO1), two regulators of the early secretory pathway, impairs GC and ERES reorganisation. This in turn results in inhibition of myotube fusion and M-cadherin (also known as CDH15) transport to the sarcolemma. Taken together, our data suggest that the correct reorganisation of the early secretory pathway components plays an important role in SKM differentiation and, thus, associated pathologies.

A New Look at the Functional Organization of the Golgi Ribbon

“…Currently, two alternatives have been considered regarding the nature of the ERES-Golgi units of myofibers. Either the Golgi ministacks emerging at these sites are formed de novo , due to recycling of Golgi components via the ER, or correspond to pre-existing elements derived from the fragmented Golgi ribbon that redistribute throughout the muscle cells (Lu et al, 2001; Zaal et al, 2011; Giacomello et al, 2019). As a compromise, we propose that repositioning of the permanent IC and endosomal networks provides the driving force for the rearrangement of the endomembrane system in muscle cells, including formation of the small Golgi stacks.…”

“…First, there is evidence that both IC elements and endosomes are present at the same MT crossroads sites, where the Golgi elements reside (Rahkila et al, 1997; Kaisto et al, 1999; Figure 5B). Second, the IC/ cis -Golgi proteins p115 and GM130 – both Rab1 effectors – have been shown to act as master regulators in the organization of early secretory compartments during myogenesis (Giacomello et al, 2019). Third, the nucleation of MTs in mature myofibers is not affected by BFA (Oddoux et al, 2013), raising the possibility that it is accomplished by the drug-resistant IC elements and REs.…”

Bi‐allelic loss of function variants in GOLGA2 are associated with a complex neurological phenotype: Report of a second family

“…15 GOLGA2 is closely associated with endoplasmic reticulum-exit sites (ERES) in muscle and knockdown in muscle cells resulted in an impairment of the Golgi compartment and ERES reorganization and inhibition of myoblast fusion. 16 Similarly, GOLGA2 knockdown in zebrafish resulted in microcephaly and myopathy. 6 Depletion of GM130/ GOLGA2 impairs vesicle transport and leads to fragmentation of the Golgi ribbon.…”

Golgi Complex form and Function: A Potential Hub Role Also in Skeletal Muscle Pathologies?

“…In mature skeletal muscle (SKM) cells, the architectural disposition of the early secretory components is unique: the GC is formed by very small elements, localized near the nucleus and in the fiber in close association with ERES in a fiber-type dependent fashion [ 5 , 6 , 7 ]. This arrangement is the result of a reorganization process occurring during SKM differentiation, which leads to the formation of small GC elements localized near the ERES [ 5 , 6 ].…”

“…In mature skeletal muscle (SKM) cells, the architectural disposition of the early secretory components is unique: the GC is formed by very small elements, localized near the nucleus and in the fiber in close association with ERES in a fiber-type dependent fashion [ 5 , 6 , 7 ]. This arrangement is the result of a reorganization process occurring during SKM differentiation, which leads to the formation of small GC elements localized near the ERES [ 5 , 6 ]. How this process takes place is not completely clear; however, our recent work [ 5 ], in agreement with data on non-muscle cells [ 8 ], suggests that during the SKM differentiation process, the GC plays a central role in the positioning and regulation of ERES and other early secretory pathway components.…”